Nicholas Asher
email: asher@irit.fr

Alex Lascarides

A Cognitive Model for Conversation

This paper describes a symbolic model of rational action and decision making to support analysing dialogue. The model approximates principles of behaviour from game theory, and its proof theory makes Gricean principles of cooperativity derivable when the agents' preferences align.

1 Introduction [START_REF] Grice | Logic and conversation[END_REF] and Neo-Griceans model the link between dialogue processing and general principles of rational behaviour by assuming that agents abide by a strong cooperativity principle-namely, people normally believe what they say and help other agents achieve the goals that they reveal through their utterances. This principle provides cooperativity on at least two levels: a basic level that ensures coordination on the conventions governing linguistic meaning (basic cooperativity); and a level concerning shared attitudes towards what is said, including shared intentions (content cooperativity). But not all conversations are content cooperative. For example, Tomm and Dave don't share intentions in (1), taken from chat recordings of an online version of the game Settlers of Catan where players negotiate over restricted resources:

(1) a. Tomm: Got any clay to trade for sheep/wheat? b. Dave: Only got 1 and I'm holding on to it, sorry.

However, even though Settlers is a win-lose game where players' interests are often opposed, its players often do share intentions, as they must cooperate to bargain for resources they need in the game.

(2) a. William: can i get a sheep or a wheat? b.

i have too much wood. c. Cat: i can give you a wheat. d. William: good

[they exchange 1 wheat for 1 wood]

Conversely, dialogue (3) is content cooperative (and basic cooperative) on the assumption that A and B are constructing a plan to achieve the same goal-that they both eat at Chop Chop:

(3) a. A: Let's go to Chop Chop by car. b. B: But there's no parking. c. A: Then let's take the bus.

But (3b) implicates that B rejects the intention underlying (3a)-to go to Chop Chop by car. The grounds for the rejecting moves in (1) vs. (3) are different. In (1) Dave can fulfil Tomm's intention but chooses not to, presumably because of his conflicting preferences. In (3) A and B (transiently) have different intentions because of their conflicting beliefs about the optimal way to achieve a shared preference: to eat at Chop Chop.

There have been several attempts to make models of conversation that abide by Gricean principles of cooperativity formally precise; for instance, by expressing axioms in a logic that supports defeasible reasoning about the cognitive states of dialogue agents (e.g., [START_REF] Schulz | Minimal Models in Semantics and Pragmatics: Free Choice, Exhaustivity, and Conditionals[END_REF], [START_REF] Asher | Logics of Conversation[END_REF]). Such models include (default) axioms Sincerity (following Grice's maxim of Quality (Grice, 1975, p46)): if a cooperative agent says something then he normally believes it. They also include axioms at the level of intentions. For instance, the following default axiom of Strong Cooperativity is adapted from Grice's analysis of what an utterance means in cooperative conversation (Grice, 1969, p151): if an agent says something that implies he has a particular intention φ that he also intends should be recognised, then a cooperative agent should normally adopt that intention φ too (e.g., (Grosz and Sidner, 1990, p430), Asher (in press)). But such formalisations are incomplete because they do not handle cases like (1) where content cooperativity breaks down: the default axioms just given don't apply in such contexts. Nor do they predict when adopting shared intentions is optimal in a strategic setting (e.g., (2)). Furthermore, (3) shows that, rather than expressing content cooperative behaviour in terms of the default adoption of the other agents' intentions, it would be better to define it in terms of shared preferences; that way, rejection is rational when conflicting beliefs yield a different optimal way to achieve a shared preference.

This paper provides a cognitive model within which one can explore reasoning about the mental states of dialogue agents. We will derive Gricean principles of cooperativity, formalised as defeasible principles, from a characterisation of certain games, using game theory as the foundation of strategic reasoning and also as the basis for linking inferences about conversation to rational action. In game theory, agents act so as to maximise their expected utility-utility being a measure of preference, and the term expected ensuring that decisions about action are made relative to one's beliefs about what the outcomes of the actions will be, including beliefs about what other agents will do. Nevertheless, we argue in Section 2 that game theory on its own provides an incomplete picture, which makes it difficult to use to derive defeasible principles. The symbolic cognitive model presented in Section 3 addresses this problem. It provides axioms approximating rational behaviour from game theory that link dialogue actions and mental states, and its proof theory allows us to derive Gricean principles of cooperativity when the agents' preferences align. We relate this approach to prior work in Section 4 and point to future work in Section 5.

Our Model

Our model for strategic agents is one that is based on logic and on game theory. Like many others, we use a variant of a Belief Desire Intention (BDI) logic to formalise Gricean implicatures. But because we countenance misdirection and deception as features of strategic conversation, we draw a distinction between Public and Private attitudes and thus introduce a new attitude for public commitment. Speaking makes an agent publicly commit to some content [START_REF] Hamblin | Imperatives[END_REF]. Traditional mentalist models of dialogue, couched within BDI logics, equate dialogue interpretation with updating mental states: e.g., interpreting an assertion that p is equivalent to updating one's model of the speaker's mental state to include a belief in p (e.g., [START_REF] Grosz | Plans for discourse[END_REF]). But they are not equivalent in (4):

(4) a. Loreleil292: Can anyone give me some clay for some wheat? b. AMI123: Sorry have none of that!

[in fact, she has 2 clay]

We interpret (4b) as a negative answer even if we know AMI121's beliefs are inconsistent with this. To do justice to this, we follow [START_REF] Asher | Logics of Conversation[END_REF] and separate the representation and logic of dialogue content from that of cognitive states and then link them via defeasible transfer principles. This separation was originally motivated by calculable implicatures being unavailable as antecedents to surface anaphora; insincerity provides a new motivation.

In common with game theoretic models of conversation (e.g., [START_REF] Parikh | The Use of Language[END_REF]), we adopt a second principle: people say things that will maximise their expected utility. So if the Gricean maxims of conversation hold, they do so because they maximise the agents' expected utility. We also maintain that agents' preferences evolve as dialogue proceeds, at least partly because agents learn about other agents' preferences from what they say and then adjust at least some of their preferences in the light of this information. People's preferences are typically partial and get more specific or evolve as they learn more through conversation.

This last assumption poses a problem for orthodox game theory. Game theory assumes each player has a completely defined preference function over the possible actions in the game. It models uncertain and partial information that one player has about another player's preferences and the actions that other play is contemplating performing by a probability distribution over player types, where each type is associated with a complete set of actions and a complete utility function.1 Game theory, however, does not provide general principles for restricting the set of player types one needs to consider or the probability distributions over them. This gap has bite in modelling conversation, because the possible signals that grammars of natural languages allow are unbounded, as are the coherent signals in context. So dialogue agents generally face the task of isolating their game problem to a set of signals that is small enough to effectively perform inference over, but large enough to yield reliable decisions about optimal actions.

To represent dialogue processing it would be better not to remain silent on how one identifies which player types-and hence which actions and preferences-are relevant, but rather to consider a partial theory or description of the agent's preferences that is updated or revised as one learns more about the agent or one considers actions that one didn't consider before. This is what we do here. This approach yields a more compact and tractable cognitive model and a proof theory in which we can reason, in the light of new evidence, about what type of player to consider in our reasoning. Standard game-theory provides models that can verify the soundness of our proof theoretic reasoning. Whether the sentences in this theory are assigned probabilities is not terribly relevant. But what is important is that elements of this theory get revised in the light of new evidence, as [START_REF] Alchourrón | On the logic of theory change: Partial meeting contraction and revision functions[END_REF] suggest. This can either be done by conditionalising a probability distribution over new evidence, or more symbolically via a theory that incorporates general but defeasible principles about human action and the preferences that underlie them.

In our symbolic model, instead of a probability distribution over every possible complete model of the game we begin with just one partial model. We will describe this model in a way that meshes easily with inferring preferences from observing what agents do. We demonstrate one advantage of this approach here: the proof theory afforded by our symbolic axioms of rational behaviour, which approximate those from game theory, is sufficient to derive Gricean principles of cooperativity, among them the default axioms of Sincerity and Strong Cooperativity that we discussed in Section 1. We thus gain a logical link between strategic conversation and content cooperative conversation.

Cognitive Modelling

To reason about an agent's motives and actions we use a familiar modal logic: B a φ means agent a believes φ, and I a φ means a intends to bring about a state that entails φ. We assume that B a abides by the modal axioms KD45 (so its accessibility relation in the model is transitive, euclidean and serial); so an agent's beliefs are mutually consistent with one another and closed under logical consequence, and agents have total introspection on their beliefs or lack thereof. We make I a abide by the modal axiom D (so its accessibility relation in the model is serial), so contradictory intentions are ruled out. We also assume that intentions are doxastically transparent: i.e., I a φ ↔ B a I a φ is an axiom. We also need a modal operator for public commitment, which is distinct from belief: P a,D φ means agent a publicly commits to φ to the group of agents D. Following [START_REF] Asher | Commitments, beliefs and intentions in dialogue[END_REF], we make P a,D K45 (one commits to all the consequences of one's commitments and one has total introspection on commitments or lack of them). Unlike belief, commitments can be contradictory because one can declare anything.

Reasoning about mental states is inherently defeasible, so we add to our logic the weak conditional from Commonsense Entailment [START_REF] Asher | Commonsense entailment[END_REF]: A > B means If A then normally B. We call this language CL (standing for cognitive logic). This logic has many nice properties; for instance, soundness completeness and decidability [START_REF] Asher | Commonsense entailment[END_REF]. Decidability is maintained even in a dynamic version of the CL [START_REF] Asher | Reasoning dynamically about what one says[END_REF], but for the sake of simplicity we will consider the static version here.

The dialogue's logical form creates public commitments in CL: if the logical form stipulates that agent a is committed to K at turn n-so K is the content of a clause or of coherently related dialogue segments-then this makes P a,d K true in CL, where K is the CL-representation of the formula K in the separate logic of dialogue content, and D is the set of dialogue agents (how K maps to K is detailed in [START_REF] Lascarides | Agreement, disputes and commitment in dialogue[END_REF] but doesn't concern us here).2

Preferences

Besides a representation of dialogue content and BDI attitudes, we need a symbolic way of representing preferences and commitments to preferences. CP-nets [START_REF] Boutilier | Cp-nets: A tool for representing and reasoning with conditional ceteris paribus preference statements[END_REF]) provide a useful formalism for extracting commitments to preferences from utterances [START_REF] Cadilhac | Commitments to preferences in dialogue[END_REF]. Standard CP-nets capture complete information: they are a compact representation of a preference order over all the possible outcomes of actions that agents can perform. To represent partial preferences, we build a partial description of a CP-net [START_REF] Cadilhac | Commitments to preferences in dialogue[END_REF], which approximates preferences as revealed by dialogue moves. This avoids having to postulate a range of player types, each associated with complete preferences. Instead, agents will reason with and revise partial descriptions of preferences as they observe new evidence through dialogue moves.

A CP-net for an individual agent has two components: a directed conditional preference graph (CPG), which defines for each feature F its set

Food A & & B Ô Ô

Drink

The CPG Preferences for A: fish A meat fish: white A red meat: red A white Preferences for B: fish ∼ B meat fish: white B red meat: red B white

The CPTs

Figure 1: A CP-net for the food and drink game.

of parent features P a(F ) that affect the agent's preferences among the various values of F ; and a conditional preference table (CPT), which specifies the agent's preferences over F 's values for every combination of values in P a(F ) (thus CPnets have a similar structure to Bayesian belief networks [START_REF] Pearl | Probabilistic Reasoning in Intelligent Systems: Networks of Plausible Inference[END_REF]). The CP-net for a game consists of a CP-net for each player. For example, the CP-net in Figure 1 (5)

(fish, white) A (fish, red) A (meat, red) A (meat, white) {(fish, white), (meat, red)} B {(fish, red), (meat, white)}

There are efficient algorithms for identifying the (unique) optimal strategy in this case (e.g., Bonzon ( 2007)): i.e., to eat fish and drink white wine. Dialogue interpretation yields commitments to preferences that are partial. For example, by uttering (2c) Cat commits to the partial CP-net in Figure 2: In words, Cat would rather receive wood than not, and given her preference for receiving wood she would rather give wheat than sheep. This is computed recursively from the discourse structure of Cat's commitment [START_REF] Cadilhac | Commitments to preferences in dialogue[END_REF], although we don't detail the mapping here. 3 Crucially, the CP-net description in Figure 2 is partial: it doesn't reveal Cat's preferences for giving wheat or sheep in a context where she doesn't get wood-(2c) says nothing about that. Cat's actual preferences may also differ from these commitments (e.g., because of insincerity). So to choose an optimal action, agents face a complex calculation in (defeasibly) estimating an agent's complete actual preferences from commitments to them.

Accordingly, we treat the preference statements in the CP-net descriptions as formulas within a background theory that provides defeasible inferences about preferences and behaviour. Our background theory is CL; so CL must be able to express and reason about descriptions of CPnets. Specifically, we complete the partial information in a CP-net description by adding assumed preferences that defeasibly follow from it via the default axioms in CL, with agents defaulting to being indifferent among values for features for which preference information is missing en-3 We take William's and Cat's commitments in (2) to be as follows [START_REF] Lascarides | Agreement, disputes and commitment in dialogue[END_REF]). William's turn commits him to Plan-Elab(a, b), which means that he commits to the contents of both (2a) and (2b) and to (2b) elaborating a plan to achieve the goal underlying (2a) (that goal is to obtain a sheep or wheat, and the plan afforded by ( 2b) is to get one of these by trading wood). Cat's utterance (2c) commits her to Plan-Elab(π, c), where π is William's first turn (with content Plan-Elab(a, b)). [START_REF] Cadilhac | Commitments to preferences in dialogue[END_REF] recursive algorithm yields Figure 2 from Plan-Elab(π, c).

tirely. In logical terms this means we will have formulae in CL of the form: χ > (φ: ψ a ¬ψ), where χ is a well-formed formula of CL. 4 In other words, if χ is true then normally the description of a's preferences includes φ: ψ a ¬ψ (note that the antecedent χ may express information about preferences too). We'll give some examples of such formulae in the next section. Further, CL's nonmonotonic inferences about an agent's preferences may change if the range of actions that are considered to be a part of the game changes (though we forego specific examples here). Overall, through the (nonmonotonic) logic of CL's >, one can support decisions about what action to perform even if knowledge of preferences is partial.

CL can now link preferences to other propositional attitudes. Indeed, choosing optimal actions requires a link between preference and belief: since a (joint) CP-net G can include variables whose values one doesn't control, one needs to check that one's optimal state(s) are not doxastically improbable (this is a crude way of ensuring that agents act so as to maximise expected utility rather than acting with wishful thinking about what's feasible). We supply a notion of doxastic improbability in CL via its nonmonotonic consequence relation: i.e., a state is belief compliant if its negation does not defeasible follow from the premises and background theory of CL axioms. So to identify an agent's optimal belief-compliant state(s), we filter out any optimal state that is defeasibly inconsistent with his beliefs (as we mentioned in Section 3, this is decidable). Within CL this leads to the definition of a CP-solution a (φ, G) for agent a and (joint) CP-net G:

Definition 1 CP-solution a (φ, G) holds iff:
1. a is a player in the joint CP-net G; and 2. s φ for every belief-compliant optimal state s of G. I.e., where Γ is the premisesin other words, CL's background theory plus information about the mental states of the players in G-we have Γ | ∼B a ¬s, and for any state s that is strictly more optimal in G than s, Γ| ∼B a ¬s holds.

For example, if B's model of A's and his own preferences are those in Figure 1, then by Definition 1 CP-solution B (fish∧white, G) holds: while meat ∧ red is equally preferred by B, it is not belief compliant because G defeasibily entails that A will choose white and not red. We'll see this in the next section, when we use CP-solutions to define CL axioms that approximate principles of rational action from game theory.

Axioms of Rationality

To encode means-end reasoning of rational agents in our symbolic model, we need CL axioms that make agents pay-off maximisers (cf. rationality from game theory) and basic cooperative. Pay-off maximisers intend actions that are an optimal trade-off between their preferences and their beliefs about what's possible; and an agent intending ψ means in the context of his current beliefs he prefers ψ to all alternative actions. We capture these two principles with the axioms Maximising Utility Maximising Utility part (a) ensures a intends ψ only if ψ follows from all belief-compliant optimal states (by Definition 1). Indeed, agent a's intentions are conditional on all of a's beliefs (thanks to Definition 1) and all of a's preferences and those of any player that affect a's preferences. The latter property follows because the weak conditional > validates the Penguin Principle-i.e., default consequences of rules with more specific antecedents override conflicting defaults from less specific antecedents. So if a more specific game G is known to hold and it yields conflicting intentions to those resulting from G, then the intentions from G are inferred and those from G aren't. Axiom (b) likewise conditions a's preference for ψ on all his beliefs (thanks to Definition 1). It yields (default) constraints on G from intentions: if one knows I a ψ and nothing about G or about a's beliefs, then the minimal CP-net G that satisfies the default consequence is simply the global preference ψ a ¬ψ. As agents converse, each dialogue action may reveal new information about intentions, and via Maximising Utility part (b) this imposes new constraints on G. But while Maximise Utility part (b) is conservative about exactly which of a's beliefs his preference for ψ is conditioned on, his dialogue moves can reveal more precise information-e.g., the utterance I want to go to the mall to eat should be sufficient to infer eat : mall i ¬mall. A detailed algorithm for extracting preferences and dependencies among them from conversation is detailed in [START_REF] Cadilhac | Commitments to preferences in dialogue[END_REF], but the details of this aren't relevant for our purposes here.

Basic cooperativity follows from an axiom that makes all agents intend that their commitments be shared among all the other dialogue agents:

Intent to Share Commitment: (b ∈ D ∧ P a,D φ ∧ ¬P b,D φ) > P a,D I a P b,D φ
If a commits, when addressing b (among others), to content φ and b hasn't committed to this yet, then normally a is also committed to intending that b so commit. This rule captures basic cooperativity because b committing to a's commitments entails he understands a's commitments [START_REF] Clark | Using Language[END_REF]. Indeed, it captures something much stronger than basic cooperativity-an intention that your contribution be accepted by others. While this is stronger than basic cooperativity, we think it's rational even in non-cooperative dialogue contexts: why commit to content if you don't intend that others accept the commitment? In addition, we regiment a constraint on assertions proposed by (Perrault, 1990, p180), by refining this axiom for assertions: when a's address to b commits him to an assertion K, then normally P a,D I a B b K. Now let's examine more carefully the special case of Gricean cooperativity. We start by defining a Grice Cooperative game:

Definition 2 A game is Grice Cooperative (GC) just in case for any of its players a and b 1. their speech acts normally have their con-ventional purpose (e.g., they normally ask a question so as to know a true answer); and 2. (φ : ψ a ¬ψ) > (φ : ψ b ¬ψ) (i.e., the agents' preferences normally align).

We can now prove all the axioms in Fact 1.

Fact 1 Sincerity: (P a,D φ ∧ GC) > B a φ Sincerity for Intentions: (P a,D I a φ ∧ GC) > I a φ Sincerity for Preferences:

(P a,D (φ : ψ a ¬ψ) ∧ GC) > φ : ψ a ¬ψ Competence: (P a,D φ ∧ P b,D ?φ ∧ a, b ∈ D) → ((B b B a φ ∧ GC) > B b φ) Cooperativity: (b ∈ D ∧ P a,D I a φ ∧ GC) > I b φ
These axioms make any declared belief, intention or preference in a GC conversation normally an actual belief, intention or preference too (cf. the Gricean maxim of Quality (Grice, 1975, p45)). Competence makes belief transfer the norm (if b asked whether φ). This default likewise follows from Grice's Maxim of Quality as he described it in (Grice, 1989, p371): he stipulates that in order to contribute to a conversation via the Maxim of Quality, one must say what is true. To do otherwise is not to contribute inferior information; rather, it contributes no information at all. Furthermore, [START_REF] Lewis | Convention: A Philosophical Study[END_REF] argues persuasively that unless such a principle of competence forms the basis of cognitive modelling, then one cannot construct a sound philosophical argument that explains why linguistic conventions come into being in the first place, or why we assume that a speaker whom we understand is speaking the same language as we are-a hallmark of basic cooperativity. Finally, Cooperativity makes a declared individual intention normally a shared actual intention (recall the Gricean notion of utterance meaning in conversation (Grice, 1969, p151) and the corresponding notion of Strong Cooperativity from Section 1). Such principles of sincerity and cooperativity are usually taken as primitive axioms in BDI approaches to dialogue; here, we derive them when agents D are players in a joint game G that satisfies Definition 2.

Outline Proofs: Sincerity: Suppose P a,D φ and GC hold and moreover that φ expresses a proposition that is capable of being believed. Then we'll show that if all the normal GC consequences hold (see Definition 2), then B a φ must also hold.

By Intent to Share Commitment, P a,D I a B b φ defeasibly follows from our premises for any b ∈ D. By Maximising Utility and the fact that I is a D modality, I a B b φ defeasibly implies B b φ a ¬B b φ. Upon learning of a's commitment and the fact that the game is GC (in particular, clause 1 of Definition 2 means that the preference underlying a's move φ that we have just derived is a's actual preference), we infer B b φ b ¬B b φ. Assume further that belief preferences pattern after factual preferences. That is:

(B b φ b ¬Bφ) → (φ b ¬φ) (¬B b φ b Bφ) → ¬(φ b ¬φ)
So φ b ¬φ. Now suppose that ¬B a φ. Then assuming we prefer our belief actions when we have them, ¬B a φ a B a φ, and therefore ¬(φ a ¬φ). Thus the game cannot be a normal GC game, contrary to our assumptions. So B a φ. Now, Weak Deduction is a valid rule of the weak conditional > [START_REF] Asher | Commonsense entailment[END_REF]: if Γ, φ| ∼ψ, Γ| ∼ /ψ and Γ| ∼ /¬(φ > ψ) then Γ| ∼(φ > ψ). So Weak Deduction yields the desired > statement, (P a,D φ ∧ GC) > B a φ. 2. We can also derive (though we don't show it here) a stronger version of Sincerity where a doesn't believe alternatives to what he said, yielding scalar implicatures.

Sincerity for Intentions: Suppose P a,D I a φ ∧ GC. By Sincerity (which we've just proved), B a I a φ. Since intentions are doxastically transparent (i.e. B a I a φ ↔ I a φ), the result follows with an application of Weak Deduction. 2.

Sincerity for Preferences is proved in a similar way, using also the assumption that preferences are doxastically transparent. There are two choices now: either a is trustworthy or not. If a is not trustworthy, then his commitment to φ is no indication of its truth. But then there is a move (do not ask a whether φ) that would have been more advantageous for b (given that listening to someone and processing the response is a cost). So given that P b,D ?φ is the equilibrium move-in other words, this is a move that is optimal for b in that it maximises his expected utility-b must believe a to be trustworthy, and so B b φ. Using Weak Deduction thus yields Competence. 2. Cooperativity: Assume b ∈ D ∧ P a,D I a φ ∧ GC. By Sincerity for Intentions, we have I a φ.

By Maximising Utility, we can infer CP-solution a (φ, G), where G is the GC game with at least a and b as players. By GC and Competence, this defeasibly entails CP-solution b (φ, G). And so Maximising Utility yields I b φ. Using Weak Deduction gets us the desired > statement. 2.

Intention and belief transfer in a GC conversation is a default: even if preferences align, conflicting beliefs may mean agents have different CP-solutions making their intentions different too (by Maximising Utility), and Competence may apply but its consequent isn't inferred. Thus rejection and denial occur in GC dialogues (see ( 3)). On the other hand, in GC environments interpretations are normally credible: e.g., by Sincerity and Competence B's assertion (3b) yields belief transfer that there's no parking. This is a simple, symbolic counterpart to the much more elaborate result concerning credibility from [START_REF] Crawford | Strategic information transmission[END_REF].

Related Work

In contrast to Gricean formalisations in BDI logics, we have conditioned Gricean behaviour on shared preferences rather than shared intentions (see Definition 2) and we have derived Gricean axioms from a more general axiomatisation of human behaviour rather than treating them as primitive.

Signalling games provide a basis for predicting conversational implicatures (e.g., [START_REF] Parikh | The Use of Language[END_REF][START_REF] Van Rooij | Signalling games select horn strategies[END_REF]) and also insincerity-the less aligned the preferences, the less credible the signals [START_REF] Crawford | Strategic information transmission[END_REF]. But signalling models either take a signal to mean whatever it is optimal for it to mean (thereby bypassing linguistic convention) or the mapping [ [.] ] from signals to meaning is fixed and monotonic (e.g., [START_REF] Farrell | Meaning and credibility in cheap-talk games[END_REF], Franke (2010)), with pragmatic interpretations being entirely epistemic in nature: they arise when the optimal interpretation of s is distinct from [ [s] ]. Our model differs in its view of conventional meaning: while we acknowledge that some pragmatic inferences are epistemic (e.g., see Sincerity), we also believe that [ [s] ] goes beyond lexical and compositional semantics because it is constrained to be coherent [START_REF] Lascarides | Agreement, disputes and commitment in dialogue[END_REF]. But this makes computing [ [s] ] defeasible, which reflects the fact that all inferences about coherence are defeasible. So in non-cooperative conversation, an interlocutor must test rigorously his defeasible inference about what the speaker is publicly committed to, as well as test the credibility of that commitment (i.e., whether the speaker believes it). We hope that CL can model such tests, but leave this to future work.

Conclusions

We have proposed a qualitative model of cognitive reasoning with several desirable features for modelling dialogue: it supports reasoning with partial information about preferences; and it distinguishes the public commitments one makes through utterances and private mental states that affect and are affected by them. The axioms of the cognitive logic approximate rational action from game theory and compel agents to be basic cooperative. We showed that Gricean principles of sincerity and cooperativity are derivable from them when the agents' preferences nor-mally align.

We have focused here entirely on the cognitive model; linking it to dialogue content is ongoing work. The cognitive logic should also be dynamic since dialogue actions trigger changes to mental states: our static CL can be made dynamic with no cost to complexity by exploiting public announcement logic [START_REF] Asher | Reasoning dynamically about what one says[END_REF]. Finally, progress in analysing strategic conversation requires an extensive study of data in many domains: e.g., political debate, commercial negotiations, courtroom cross examination and others. The Settlers dialogues cited here are all taken from our ongoing corpus collection effort, in which utterances are aligned with machine readable game states. We hope to release this corpus, labelled with rich semantic and cognitive information, in due course.

  Figure 2: Cat's commitments to preferences in dialogue (2). Receive and Give's values are r-x and g-x where x is wheat, clay, sheep, rock or ore.

  (a) and (b): Maximising Utility: a. (G ∧ CP-solution a (ψ, G)) > I a ψ b. (I a ψ ∧player(i, G)) > CP-solution a (ψ, G)

  2. Competence: Suppose P b,D ?φ ∧ P a,D φ ∧ b ∈ D ∧ B b B a φ and a GC game. Given Definition 2, the intention that normally underlies asking a question (i.e., to know an answer) and Maximising Utility ensures that b's asking φ implies B b φ ∨ B b ¬φ b ¬(B b φ ∨ B b ¬φ). So by GC (i.e., the agents' preferences normally align), we also have: B b φ ∨ B b ¬φ a ¬(B b φ ∨ B b ¬φ). By Maximising Utility we can assume that b's asking a question together with a's response are both optimal moves in equilibrium. These moves then should realise the preference B b φ ∨ B b ¬φ b ¬(B b φ ∨ B b ¬φ). Furthermore, by Sincerity, B a φ.

Game theory allows players to have imperfect knowledge of what action other players play, but that is not relevant here.

K captures all a's current commitments, including ongoing commitments from prior turns. So there is no need to conjoin an agent's commitments from each turn in CL.

Since the features in our CP-nets all take finite values, they can be represented in CL using Boolean variables.

Acknowledgements: This work is supported by ERC grant 269427 (STAC).


Céline Anquetil

Joe-Elie Salem

Bénédicte Lebrun-Vignes

Sara Touhami

Anne-Claire Desbois

Georgina Maalouf

Fanny Domont

Yves Allenbach

Patrice Cacoub

Bahram Bodaghi

M.D David Saadoun
email: david.saadoun@aphp.fr

Evolving spectrum of drug-induced uveitis at the era of immune checkpoint inhibitors results from the WHO's pharmacovigilance database

Keywords: drug induced-adverse event, uveitis, immune checkpoint inhibitors, protein kinase inhibitors, visual loss

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Introduction

Uveitis represents one of the leading causes of visual deficit and handicap worldwide. Uveitis is defined by an inflammation of the uveal tract of the eye (including the iris, the ciliary body, and the choroid). Usually, uveitis is classified according to the location of the inflammation (anterior, intermediate, posterior or panuveitis). It is thought to be responsible for 5% of legal blindness cases, owing mainly to its complications including macular alterations, glaucoma and retinal ischemia [START_REF] Suttorp-Schulten | The possible impact of uveitis in blindness: a literature survey[END_REF]. At the 10-year follow-up, 20% of the patients suffered from some degree of visual loss [START_REF] Tomkins-Netzer | Longterm clinical outcome and causes of vision loss in patients with uveitis[END_REF]. The reported prevalence of uveitis varies from 24.9 cases to 52.4 cases per 100,000 person-years depending on the ethnicity [START_REF] Acharya | Incidence and Prevalence of Uveitis: Results From the Pacific Ocular Inflammation Study[END_REF][START_REF] Gritz | Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study[END_REF]. Moreover, uveitis is more frequent in middle-aged populations though long-term visual loss is a major concern in this population. The cause of uveitis depends on several factors such as ethnicity and geographic origin, age, gender, genetic factors such as HLAtypes [START_REF] Tsirouki | A Focus on the Epidemiology of Uveitis[END_REF], and localization of inflammatory reactions (anterior, posterior, panuveitis) [START_REF] Thorne | Prevalence of Noninfectious Uveitis in the United States: A Claims-Based Analysis[END_REF]. While infectious causes represent the first etiology in developing countries (30-50%), non-infectious uveitis is more prevalent in the western world [START_REF] Tsirouki | A Focus on the Epidemiology of Uveitis[END_REF]. Despite extensive workup, 30-60% of uveitis cases remain undiagnosed. Drug-induced uveitis represents a rare cause of uveitis, estimated at 0.3 to 0.5% of all cases [START_REF] Chen | Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) -Report 1: Epidemiology and Classification[END_REF]. Over the last decade, the spectrum of drugs inducing uveitis has evolved paralleling the evolution of pharmacopeia. In the '90s, anti-infectious treatments were the most common causal drugs including cidofovir and rifabutin [START_REF] Ambati | Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis[END_REF][START_REF] Frank | Rifabutin and Uveitis[END_REF]. More recently, drug-induced uveitis have been reported after the use of new anti-cancer treatments such as protein kinase inhibitors and immune checkpoint inhibitors (ICI) [START_REF] Guedj | Uveitis in patients with late-stage cutaneous melanoma treated with vemurafenib[END_REF][START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF]. In the pivotal clinical trials of ICI, ophthalmic adverse events occurred rarely between 0.4 to 1% of patients [START_REF] Hodi | Improved survival with ipilimumab in patients with metastatic melanoma[END_REF]. However, only a few series of case reports have been published [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF][START_REF] Aaberg | PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS[END_REF][START_REF] Bitton | Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy[END_REF]. Having in mind the fact that the population exposed to these new drugs will be increasing, there is an urgent need for a better and systematic characterization of their adverse events. This study aims to describe the spectrum of drug-induced uveitis using an international case safety report database. By gathering a large number of cases, we expect to obtain a more accurate picture of these adverse events.

Methods

Study design

The study is a disproportionality analysis based on adverse drug reactions (ADR) reported within VigiBase, the WHO global deduplicated database of Individual Case Safety Report (ICSR) [START_REF] Lindquist | VigiBase, the WHO Global ICSR Database System: Basic Facts[END_REF]. VigiBase contains over 20,000,000 ICSRs of suspected medication ADR (as of 01/2019) submitted by national pharmacovigilance centers from more than 130 countries since 1967. These reports originate from different sources such as physicians or other healthcare professionals, pharmaceutical companies, and patients, and generally occur post-marketing.

Procedure

This observational pharmacological retrospective study included all ICSRs reported as 'uveitis' at Preferred Term level according to the Medical Dictionary for Drug Regulatory Activities (MedDRA) between 1967 and 04/28/2019. The drugs included in the analysis were reported as 'suspected' in VigiBase and we focused on the drugs with systemic administration. Drugs with potential indication and protopathic bias were excluded from analysis and the corresponding list of excluded drugs can be found in supplementary Table 1. Each ICSR contains general administrative information (reporter qualification, date of reporting, country of origin), patient characteristics (age, sex), drugs (indication for the drug, dosage regimen, start and end dates, route of administration) and reactions/events (reported terms, MedDRA classification terms, onset date, end date, seriousness, outcome).

Statistical analysis

VigiBase allows for case/non-case analysis (disproportionality analysis) which we utilized to study if suspected drug-induced uveitis were differentially reported for each suspected treatment compared to the full database. Disproportionality is calculated by the information component (IC) when using the entire database as a comparator. Calculation of the IC, using a Bayesian confidence propagation neural network, was specifically developed and validated by Uppsala Monitoring Centre as an automated, flexible indicator value for disproportionate reporting that compares expected and observed adverse drug reactions associations to find new drug-ADR signals with identification of probability difference from the background data (full database) [START_REF] Bate | A Bayesian neural network method for adverse drug reaction signal generation[END_REF]. The statistical formula is as follows, IC = log2 ((Nobserved+0•5)/(Nexpected+0•5) where Nexpected = (Ndrug*Neffect) / Ntotal and Nexpected is the number of case reports expected for the drug-adverse effect combination; Nobserved is the actual number of case reports for the drug-adverse effect combination; Ndrug is the number of case reports for the drug, regardless of adverse effects; Neffect: the number of case reports for the adverse effect, regardless of drug; and Ntotal: the total number of case reports in the database. IC025 is the lower end of a 95% credibility interval for the IC. A positive IC025 (>0) is deemed significant [START_REF] Norén | Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery[END_REF]. Further details concerning these statistical aspects and examples of utilisations have recently been published elsewhere [START_REF] Salem | Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study[END_REF][START_REF] Arnaud | Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database[END_REF][START_REF] Mertz | Characterizing drug-induced capillary leak syndromes using the World Health Organization VigiBase[END_REF][START_REF] Johnson | Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study[END_REF]. Characteristics of cases were described in terms of medians (with interquartile range) for quantitative variables, and effective and proportion for qualitative ones. Comparisons were performed using Chi2-test or Kruskal-Wallis with Dunn's post-test, when appropriate. Time to onset was compared using the Log-rank test. P-value<0.05 was deemed significant. Analyses were performed using Graphpad Prism 6 (GraphPad Software Inc., San Diego, CA, USA).

Results

The spectrum of drug-induced uveitis in Vigibase

Since 1967, uveitis has been reported at least once as an ADR for 674 suspected drugs in VigiBase, of which 111 drugs presented a significant over-reporting signal corresponding to a positive IC025 value. We extracted 1,404 ICSRs corresponding to 37 drugs with systemic administration and after excluding treatments with potential indication or protopathic biases (Table 1).

The ICSRs originated mostly from Europe (45.3%), and the Americas (38.2%). The majority of ICSRs were reported by healthcare professionals (88.9%, n=976/1,098). The median age was 57 years (n=1,084/1,404), 45.7% of cases were males (n=582/1,274). A severe visual loss was reported in 12.1% of ICSRs. When reported, the cause of death was related to malignant progression (n=7) or other drug reaction (n=6) including myocarditis, acute renal failure. The overall mortality rate was 1.7%. Over the years, we saw a switch of causal drugs. Anti-cancer drugs (ICI and protein kinase inhibitors) were the most recently emerging signals for drug-induced uveitis (p<0.001) (Figure 1).

Clinical characteristics depending on the drug

We identified five groups of treatments gathering the majority of the ICSRs: bisphosphonates (n=377/1,404, 26.9%), non-antiviral anti-infectious drugs (n=356/1,404, 25.4%), protein kinase inhibitors (n=217/1,404, 15.5%), ICI (n=211/1,404, 15.0%), and antiviral drugs (n=156/1,404, 11.1%). We summarized the clinical characteristics of each group in Table 2. We identified significant differences in terms of median age of uveitis occurrence (p<0.0001) and sex ratio (p<0.0001) between the groups. These differences may be explained by the drug indication. For instance, in the bisphosphonate group, patients were women in 81.3% of the cases with a median age of 65 years [58-73] and the principal indication of the treatment was osteoporosis. Associated ophthalmologic symptoms were poorly reported. However, we identified 19 conjunctivitis and 25 scleritis/episcleritis cases in the bisphosphonate group, whereas it was not reported in the other groups. The time to onset between first treatment administration and uveitis was significantly different between the 5 groups ranging from 5 days [START_REF] Tomkins-Netzer | Longterm clinical outcome and causes of vision loss in patients with uveitis[END_REF][START_REF] Acharya | Incidence and Prevalence of Uveitis: Results From the Pacific Ocular Inflammation Study[END_REF][START_REF] Gritz | Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study[END_REF][START_REF] Tsirouki | A Focus on the Epidemiology of Uveitis[END_REF][START_REF] Thorne | Prevalence of Noninfectious Uveitis in the United States: A Claims-Based Analysis[END_REF][START_REF] Chen | Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) -Report 1: Epidemiology and Classification[END_REF][START_REF] Ambati | Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis[END_REF][START_REF] Frank | Rifabutin and Uveitis[END_REF][START_REF] Guedj | Uveitis in patients with late-stage cutaneous melanoma treated with vemurafenib[END_REF][START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF][START_REF] Hodi | Improved survival with ipilimumab in patients with metastatic melanoma[END_REF][START_REF] Aaberg | PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS[END_REF][START_REF] Bitton | Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy[END_REF][START_REF] Lindquist | VigiBase, the WHO Global ICSR Database System: Basic Facts[END_REF][START_REF] Bate | A Bayesian neural network method for adverse drug reaction signal generation[END_REF][START_REF] Norén | Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery[END_REF][START_REF] Salem | Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study[END_REF][START_REF] Arnaud | Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database[END_REF] in the bisphosphonate group to 138.5 days [47.25-263.75] in the protein kinase inhibitors group (p<0.0001) (Figure 1). Bisphosphonate-induced uveitis occurred significantly earlier than the other druginduced uveitis in a multivariate analysis (p<0.0001). No difference was identified between the other drugs (antiviral drugs median time to onset 68 days , ICI median time to onset 76 days , non-antiviral anti-infectious drugs 136 days , and protein kinase inhibitors 138.5 days [47.25-263.75]).

Prognosis of drug-induced uveitis

Drug-induced uveitis was reported as a serious ADR in 31.8 -58.1% of the ICSRs. A severe visual loss (defined by the terms listed in supplementary table 2) was reported in 5.2% of cases (n=11/211) in the ICI group, 9.7% of cases (n=21/217) in the protein kinase inhibitor group, 9.8% of cases (n=37/377) in the bisphosphonate group, 14.6% of cases (n=52/356) in the non-antiviral anti-infectious drug group, and 17.9% (n=28/156) of cases in the antiviral drug group (p=0.0005).

Focus on ICI-induced uveitis

We identified 211 ICSRs of ICI-induced uveitis. Included patients received ICI monotherapy by anti-Programmed Cell Death 1 (anti-PD1: nivolumab n=87/211, pembrolizumab n=61/211) and by anti-Cytotoxic T-Lymphocyte-Associated Antigen 4 (anti-CTLA4: ipilimumab n=30/211). Combined immunotherapy (n= 33/211) represented 15.6% of the ICSRs. ICI were almost exclusively reported as the only suspected drugs in these ICSRs (n=195/211, 92.4%). Melanoma was the main indication of ICI therapy (n=116/211, 55.0%) followed by lung and renal cancers (respectively 17.5% and 9.0%). ICI-induced uveitis was associated with other immune-related adverse events especially cutaneous (10.4%), endocrine (9.0%), neurologic (8.5%), rheumatologic (8.2%), and gastro-enterologic (7.1%) (defined by the terms listed in supplementary table 2).

We identified 8 cases of drug-induced Vogt-Koyanagi-Harada syndrome (VKH) with anti-cancer drugs mainly with ICI in 6 cases and a combination of dabrafenibtrametinib in the other 2 cases. The median age in these cases was 45 years [39.3-67.8]; the sex ratio female/male was 3/1. The drug indication was melanoma in 6 ICSRs, lung cancer in 1 ICSR, and 1 was unknown. In one case, a severe visual loss was reported.

Discussion

We report here the largest series of drug-induced uveitis cases with a total of 1,404 deduplicated ICSRs involving 37 different and significantly associated drugs. As expected, the profile of drugs changed overtime following the development of new treatments with the emergence of protein kinase inhibitors and ICI as the main purveyors of uveitis in recent years. Importantly, positive signals described in this study with our agnostic approach were consistent with the previously confirmed reports of drug-induced uveitis, with liability of anti-infectious agents such as rifabutin, cidofovir, and less frequently clarithromycin and moxifloxacin described in small series in the '90s [START_REF] London | Drug-induced uveitis[END_REF]. Interestingly, differences in terms of demographic characteristics, time to onset and prognosis were found between drugs. These differences may reflect the characteristics of the exposed population to a specific drug according to the treatment indication. For instance, bisphosphonates are frequently used to treat osteoporosis leading to a high proportion of female patients. However, these disparities may also be due to the impairment of different pathways depending on the drugs which is reflected by the difference in terms of time to onset. The median time to onset of uveitis ranged from 5 days with bisphosphonates to 138.5 days with protein kinase inhibitors. Finally, in our study, 35 to 58% of the uveitis were considered serious adverse events and 5.2 to 17.9% of patients experienced severe visual loss defined by the MedDRA terms listed below.

The visual prognosis of drug-induced uveitis depends on the therapeutic molecule. In a prospective study, the incidence of zoledronate-induced uveitis was 1.1% with mildmoderate acute anterior uveitis except for one severe case. At the end of follow-up, no vision loss nor long-term sequelae were reported [START_REF] Patel | Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial[END_REF]. In a case series of 7 patients with ICI-induced uveitis, the uveitis presentation varies and the visual prognosis too. One case presented an irreversible visual loss despite aggressive treatment and one patient died while being treated for uveitis [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF]. In our series, we found also several deaths related to other immunotoxicities or malignant progression in patients with ICI-induced uveitis. The severity and the frequency of immunotoxicities vary depending on the site and the therapeutic target [START_REF] Wang | Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis[END_REF]. Cardiovascular immunotoxicities are severe with a mortality rate of 50% in case of myocarditis. Also, ICI-induced temporal arteritis was associated with 30% of permanent blindness [START_REF] Salem | Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study[END_REF].

The pathophysiology of drug-induced uveitis is not fully understood and depends on the cellular pathway targeted by each drug. While direct toxicity has been reported for cidofovir therapy, autoimmune and immune-mediated responses are the likely causal pathways of ICI-induced uveitis. Cidofovir is a cytomegalovirus (CMV) nucleoside analog that blocks DNA polymerase and disrupts DNA replication of CMV by competitive mechanisms. The first published series reported 26-89% of cidofovirinduced uveitis occurring after 4-11 injections which is consistent with our findings in terms of time to onset and signal detection [START_REF] Ambati | Anterior uveitis associated with intravenous cidofovir use in patients with cytomegalovirus retinitis[END_REF][START_REF] Chavez-De La Paz | Anterior nongranulomatous uveitis after intravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention[END_REF][START_REF] Bainbridge | Ocular complications of intravenous cidofovir for cytomegalovirus retinitis in patients with AIDS[END_REF]. In our study, two other classes of antiviral molecules were associated with an over-reporting signal: protease inhibitors (ritonavir, ritonavir-lopinavir, indinavir, nelfinavir, saquinavir) and nucleoside reverse transcriptase inhibitors (lamivudine, didanosine, stavudine, abacavirlamivudine). Assessing the causality link between these drugs and the ocular toxicity remains complicated due to various confounding factors. These treatments are coprescribed in the highly active antiretroviral therapy regimen and may be associated with other drugs such as rifabutin or cidofovir. Though, three cases of uveitis were reported under protease inhibitors treatment with in fact, an increased systemic level of rifabutin due to interaction with the highly active antiretroviral therapy [START_REF] Gariano | Uveitis following administration of the protease inhibitor indinavir to a patient with AIDS[END_REF][START_REF] Ebraert | Toxic uveitis caused by pharmacodynamic interactions of Rifabutin and protease inhibitors: a case report[END_REF][START_REF] Cheng | Bilateral uveitis associated with concurrent administration of rifabutin and nelfinavir[END_REF].

Bisphosphonates have been reported in large retrospective cohorts as a uveitis risk factor [START_REF] Etminan | Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study[END_REF]. Potential pathological mechanisms may involve the release of proinflammatory cytokines (TNFα, IL6) [START_REF] Russell | Bisphosphonates: Mode of Action and Pharmacology[END_REF]. In our study, we reported a very short time to onset of uveitis after initiation of treatment which is consistent with this acute phase response mechanism.

New anti-cancer immunotherapies target the immune checkpoints CTLA-4 for ipilimumab and PD-1/PD-L1 (Programmed Cell Death Ligand 1) axis for nivolumab and pembrolizumab. By activating the lymphocytes, thereby restoring the anti-tumor immune response, these drugs may also induce a break of tolerance leading to immune-related adverse events. Case reports and small series recently reported ICIinduced uveitis amongst other inflammatory ocular toxicities such as dry eye and orbital inflammation [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF][START_REF] Samra | A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab[END_REF][START_REF] Baughman | Bilateral Uveitis and Keratitis Following Nivolumab Treatment for Metastatic Melanoma[END_REF][START_REF] Touhami | Neoplasia and intraocular inflammation: From masquerade syndromes to immunotherapy-induced uveitis[END_REF]. In the largest retrospective series, uveitis was reported in 7 patients after ICI treatment (pembrolizumab n=3, nivolumab n=1, nivolumab plus ipilimumab n=2, and atezolizumab n=1) [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF]. In this study, patients were treated for melanoma (n=5), lung adenocarcinoma (n=1), and colon adenocarcinoma (n=1). All cases had bilateral uveitis. Steroids controlled the inflammation in 85.7% of cases and 1 patient presented severe vision loss despite systemic steroids [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF]. Other papers reported a wide spectrum of ophthalmologic immune-related adverse events ranging from dry eye to orbital inflammation [START_REF] Bitton | Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy[END_REF][START_REF] Touhami | Neoplasia and intraocular inflammation: From masquerade syndromes to immunotherapy-induced uveitis[END_REF]. In the literature, ICI-induced uveitis occurred after 6 to 12 weeks of treatment which is consistent with our findings (median time of 76 days) [START_REF] Conrady | Checkpoint inhibitor-induced uveitis: a case series[END_REF][START_REF] Baughman | Bilateral Uveitis and Keratitis Following Nivolumab Treatment for Metastatic Melanoma[END_REF][START_REF] Papavasileiou | Ipilimumab-induced Ocular and Orbital Inflammation--A Case Series and Review of the Literature[END_REF]. This time to onset is longer than with other severe ICI toxicities such as myocarditis or myositis which appear after 1 to 2 injections [START_REF] Salem | Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study[END_REF]. This time to onset of 3 months could be compared to the development of ocular graft versus host disease [START_REF] Sun | Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life[END_REF]. Of note, in graft versus host disease, several ocular manifestations have been reported such as dry eye, conjunctivitis, blepharitis, and less frequently uveitis with other organ involvements especially the skin [START_REF] Westeneng | Ocular graft-versus-host disease after allogeneic stem cell transplantation[END_REF].

We report here the largest case series of ICI-induced uveitis with 211 ICSRs. In line with the data already published, most patients received anti-PD1 treatment for melanoma. Based on the results of the clinical pivotal trials, the expected incidence of ICI induced-uveitis is less than 1% [START_REF] Robert | Pembrolizumab versus Ipilimumab in Advanced Melanoma[END_REF][START_REF] Antonia | Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial[END_REF]. ICI and protein kinase inhibitors were the only drugs associated with a peculiar form of uveitis, VKH syndrome. It is a systemic inflammatory disorder combining a bilateral chronic granulomatous panuveitis with central nervous system, auditory and integumentary (alopecia, vitiligo, poliosis) manifestations [START_REF] Read | Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature[END_REF]. In the literature, few case-reports have also reported VKH or VKH-like syndrome induced by ICI (nivolumab, pembrolizumab or ipilimumab) or by protein kinase inhibitors (vemurafenib, encorafenib, binimetinib) [START_REF] Crosson | Vogt-Koyanagi-Harada-like Syndrome After CTLA-4 Inhibition With Ipilimumab for Metastatic Melanoma[END_REF][START_REF] Bricout | Vogt-Koyanagi-Harada-like Syndrome Complicating Pembrolizumab Treatment for Metastatic Melanoma[END_REF][START_REF] Diamantopoulos | Incomplete Vogt-Koyanagi-Harada disease following treatment with encorafenib and binimetinib for metastatic melanoma[END_REF][START_REF] Fujimura | HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy[END_REF][START_REF] Obata | Vogt-Koyanagi-Harada Disease-Like Uveitis during Nivolumab (Anti-PD-1 Antibody) Treatment for Metastatic Cutaneous Malignant Melanoma[END_REF][START_REF] Matsuo | Vogt-Koyanagi-Harada disease-like posterior uveitis in the course of nivolumab (anti-PD-1 antibody), interposed by vemurafenib (BRAF inhibitor), for metastatic cutaneous malignant melanoma[END_REF][START_REF] Fusumae | Vogt-Koyanagi-Harada disease-like uveitis induced by vemurafenib for metastatic cutaneous malignant melanoma[END_REF], although the drug-induced form of VKH syndrome sometimes lacked the neurological, auditory or cutaneous symptoms [START_REF] Matsuo | Vogt-Koyanagi-Harada disease-like posterior uveitis in the course of nivolumab (anti-PD-1 antibody), interposed by vemurafenib (BRAF inhibitor), for metastatic cutaneous malignant melanoma[END_REF][START_REF] Fusumae | Vogt-Koyanagi-Harada disease-like uveitis induced by vemurafenib for metastatic cutaneous malignant melanoma[END_REF]. Regarding the ocular symptoms, patients presented either early or late manifestations of VKH syndrome [START_REF] Bricout | Vogt-Koyanagi-Harada-like Syndrome Complicating Pembrolizumab Treatment for Metastatic Melanoma[END_REF] and usually improved following steroids and discontinuation of immunotherapy. Interestingly, most reported patients were treated for melanoma confirming the immune-mediated pathophysiologic mechanism of uveitis during ICI therapy. It has been reported that both CD4+ and CD8+ T cells play a crucial role in the pathogenesis of the disease by the recognition of human melanocytes and melanoma antigens [START_REF] Sugita | Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma antigen in HLA-A2 patients with Vogt-Koyanagi-Harada disease[END_REF][START_REF] Sugita | Ocular infiltrating CD4+ T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens[END_REF]. In the case of melanoma, highly ICI-activated lymphocytes mediate the anti-cancer response but also the immune-related adverse events with a major tropism for tissues or organs containing melanocytes such as the eye, hair, skin, inner ear and choroidal plexi, all of which being potentially affected in VKH syndrome. Malignant melanoma cells and normal choroidal melanocytes may share a target epitope for T-cell recognition.

The PD-L1 molecule is constitutionally expressed in the retinal pigment epithelium, corneal epithelium and endothelium [START_REF] Yang | PD-L1 Expression on Human Ocular Cells and Its Possible Role in Regulating Immune-Mediated Ocular Inflammation[END_REF]. In in vitro models, CD4+ T cell proliferation was negatively regulated by cell-to-cell contact between T cells and human corneal endothelial cells through PD-1/PD-L1 interaction [START_REF] Sugita | Human corneal endothelial cells expressing programmed death-ligand 1 (PD-L1) suppress PD-1+ T helper 1 cells by a contactdependent mechanism[END_REF]. Altogether, these data suggest a potential role of the PD-1/PD-L1 axis in contributing to the immune-privileged status of the eye.

This study has several limitations due to its design and the use of a declarative pharmacovigilance database. Uveitis was defined as a reported preferred term in the database and we could not review the cases to confirm the diagnosis or reassess the liability of the drug in the occurrence of uveitis. However, this worldwide database allows aggregating the largest series of drug-induced uveitis.

In conclusion, drug-induced uveitis is a rare but potentially sight-threatening adverse event. With the rapid development of ICI therapy, physicians should be aware of its specific ocular toxicity. VKH-like syndrome represents a peculiar form induced by immune checkpoint inhibitors and/or protein kinase inhibitors, particularly in the context of melanoma. Drug-induced uveitis may represent a model to understand auto-immune uveitis development and help to find new treatment targets.

FiguresFigure 1 .

 1 Figures Figure 1. Distribution of the reported uveitis individual case safety reports (ICSRs) according to the entry date in VigiBase for the 5 main groups of drugs.Relative frequency distribution represents the percentage of the ICSR per year of reporting for each of the 5 mains suspected groups of drugs over the total number of uveitis ICSR per group.

Figure 2 .

 2 Figure 2. Time to onset for the main 5 groups of drugs. n represents the number of individual case safety reports with available time to onset data.

Figure 3 .

 3 Figure 3. The overlap between the five groups of drugs identified as signals of druginduced uveitis. Venn diagram identifying the number of uveitis cases with several suspected drugs

Table 1 :

 1 List of the 37 drugs with a significant over reporting (defined by a positive IC025 value) for uveitis (n=5,500 total uveitis ICSRs) in VigiBase (n=19,414,607 total ICSRs) through 04/28/2019.

	Substance	ATC	Nobserved	Nsubstance	Ncountry	IC025	Nserious (%)	Nblindness (%)	Known/Unknown
	Non-antiviral anti-infectious drugs								Known
	Rifabutin	J04AB04	265	1,436	21	8.01	66 (24.9)	32 (12.1)	Probable
	Clarithromycin	J01FA09	74	43,156	11	2.20	31 (41.9)	9 (12.2)	Possible
	Moxifloxacin	J01MA14 61	35,392	9	2.16	53 (86.9)	16 (26.2)	Possible
	Ethambutol	J04AK02	29	25,852	5	1.34	8 (27.6)	5 (17.2)	Possible
	Fluconazole	J02AC01	13	19,913	7	0.25	3 (23.1)	0 (0)	Possible
	Trimethoprim	J01EA01	8	9,686	4	0.22	4 (50.0)	0 (0)	Probable
	Antiviral drugs								Known
	Cidofovir	J05AB12	83	867	11	6.48	21 (25.3)	12 (14.5)	Probable
	Indinavir	J05AE02	24	7,561	4	2.58	3 (12.5)	8 (33.3)	Possible
	Ritonavir	J05AE03	23	14,707	5	1.68	10 (43.5)	2 (8.7)	Possible
	Stavudine	J05AF04	24	17,168	6	1.56	7 (29.2)	9 (37.5)	Possible
	Lamivudine	J05AF05	28	21,322	7	1.54	10 (35.7)	15 (53.6)	Possible
	Nelfinavir	J05AE04	9	3,896	4	1.47	3 (33.3)	1 (11.1)	Possible
	Saquinavir	J05AE01	7	2,622	2	1.33	1 (14.3)	1 (14.3)	Possible
	Didanosine	J05AF02	10	6,799	3	1.08	4 (40.0)	4 (40.0)	Possible
	Lopinavir;Ritonavir	J05AR10	10	10,103	4	0.61	7 (70.0)	2 (20)	Possible
	Abacavir;Lamivudine	J05AR02	5	4,792	4	0.43	4 (66.7)	0 (0)	Possible

Table 2 :

 2 Characteristics of individual case safety reports according to the suspected group of drugs

	Global	Immune	Bisphosphonates	Protein kinase inhibitors	Antiviral drugs	Other anti-
	characteristics	checkpoint				infectious
		inhibitors				drugs
		N=211	N=377	N=217	N=156	N=356
	Age *	65 [54-71]	65 [58-73]	59 [48.75-68]	40 [35-46]	44 [35-57.5]
	year, median IQR
	Sex
	Men	110/191 (57.6)	67/359 (18.7)	92/194 (47.4)	104/131 (79.4)	184/314 (58.6)
	Women	81/191 (42.4)	292/359 (81.3)	102/194 (52.6)	27/131 (20.6)	130/314 (41.4)
	Reporter qualification
	Health
	professional

* data available: ICI n=144/211, bisphosphonates n=310/377, oncological drugs n=136/217, antiviral drugs n=122/156, other anti-infectious n=304/356 IQR: interquartile range

sources. The likelihood of a causal relationship is not the same in all reports. The information does not represent the opinion of WHO.

Availability of data and materials:

The datasets analyzed during the current study are available on Vigibase website (http://www.vigiaccess.org/). The methods used in the article, including the preferred terms and drug names are outlined in the paper.

Nblindness: The number of VigiBase ICSRs with severe visual loss according to the definition in supplementary Table 2.

Association of these drugs with uveitis was categorized as follow: Definite: drugs definitely inducing uveitis based on matched case-control studies; Probable: drugs possibly inducing uveitis based on reports in cohorts;

Possible: drugs possibly inducing uveitis based on case reports (≤10 cases)


Barbara Gili Fivela
email: barbara.gili@ateneo.unile.it

Claudio Zmarich
email: zmarich@pd.istc.cnr.it

Pascal Perrier^
email: perrier@icp.inpg.fr

Christophe Savariaux°
email: christophe.savariaux@icp.inpg.fr

Graziano Tisato
email: gtisato@pd.istc.cnr.it

ACOUSTIC AND KINEMATIC CORRELATES OF PHONOLOGICAL LENGTH CONTRAST IN ITALIAN CONSONANTS

Keywords: length contrast, geminates, kinematics, Italian, consonants

In Italian, length contrast is exploited in the consonant system. Previous articulatory studies have focused on the temporal organization of gestures in Italian geminates and on the lower lip kinematics of the singleton/geminate distinction. In this paper, data on lip and tongue gestures are discussed in order to directly test hypotheses on the gestural organization of geminate consonants and to collect observations on the possible position of gestural targets in geminate and singleton consonants. The results show that Italian geminates appear to be best accounted for by a hybrid model that makes use of both Öhman"s Vowel-to-Vowel model and Browman and Goldstein"s Vowel-and-Consonant model. Moreover, our data partly confirm the existence of a higher virtual target in geminates than in singletons.

INTRODUCTION

The phonetic characteristics of geminate consonants in Italian have been reported in a number of papers, especially as far as acoustic and auditory features are concerned. Various studies show that geminate consonant duration is about twice singleton duration, and that the vowel immediately preceding a geminate consonant is shorter than the vowel preceding a singleton [START_REF] Bertinetto | Strutture prosodiche dell'italiano[END_REF][START_REF] Esposito | Acoustical and perceptual study of gemination in italian stops[END_REF]. The first kinematic study taking account of Italian geminates [START_REF] Smith | Prosodic patterns in the coordination of vowel and consonant gestures[END_REF] focused on the temporal organization of consonantal gestures with respect to vowels and showed that Italian geminates are better represented by the Vowel-to-Vowel model proposed by Öhman [START_REF] Öhman | Numerical Model of Coarticulation[END_REF] than by the Vowel and Consonants model of Browman and Goldstein [START_REF] Browman | Towards an articulatory phonology[END_REF]. Other studies [START_REF] Zmarich | Consonanti scempie e geminate in italiano: studio cinematico e percettivo dell"articolazione bilabiale e lebiodentale[END_REF][START_REF] Gili Fivela | Italian Geminates under Speech Rate and Focalization Changes: Kinematics, Acoustic, and Perception Data[END_REF], focusing on the monosegmental vs. bisegmental representation of geminates and on the kinematics of lower lip gesture, have provided evidence for the heterosyllabic representation of geminate consonants, due to their similarity with heterosyllabic clusters. In fact, kinematic measurements show that the opening gesture has longer duration, greater amplitude and time-topeak, and lower stiffness in both geminates and cluster segments than in singleton consonants.

This work stems from the above-mentioned comparisons of Italian geminate and singleton consonants. The goal of this paper is to discuss data on a wider range of gesture types (both lip and tongue gestures), and to directly test some hypotheses concerning the gestural organization of geminate consonants. First of all, the aim is to directly test Smith"s hypothesis [START_REF] Smith | Prosodic patterns in the coordination of vowel and consonant gestures[END_REF] on the temporal organization of gestures in Italian geminate consonants, and secondly, to collect observations on the possible position of gestural targets in geminates and singleton consonants. We will consider Löfqvist"s [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF] suggestion that a higher virtual target could underlie the production of geminate as compared to singleton consonants.

GESTURE TEMPORAL ORGANIZATION AND GESTURE TARGET

According to Smith [START_REF] Smith | Prosodic patterns in the coordination of vowel and consonant gestures[END_REF], in syllable-timed languages such as Italian, the time interval between the nuclei of two successive syllables does not depend on the number of intervening consonants. Smith's data from three Italian speakers, producing bilabial consonants in an /i/-to-/a/ vowel context, support the hypothesis that in geminate consonants the closure gesture is anticipated during the preceding vowel and the opening gesture is postponed during the following vowel, while the centre of maximum constriction is timed similarly for both types of consonant. According to Smith, the model which best accounts for vowel and consonant gesture timing in Italian is Öhman"s [START_REF] Öhman | Numerical Model of Coarticulation[END_REF] Vowel-to-Vowel model, where the consonant gesture is considered to be superimposed on a vowel-to-vowel gesture which determines the basic timing. In contrast, in a language such as Japanese, which is not syllable-timed, temporal gesture organization seems to be best represented by Browman and Goldstein"s [START_REF] Browman | Towards an articulatory phonology[END_REF] Vowel-and-Consonant model. Indeed, the vowel gesture starts at the end of the consonantal one, meaning that both the time interval between the two vocalic nuclei and the timing of maximum consonantal constriction depend on the number of intervening consonants (for Japanese, see also [START_REF] Löfqvist | Interarticulator programming: Effects of closure duration on lip and tongue coordination in Japanese[END_REF]).

Smith"s hypothesis was tested for Italian by Zmarich and Gili Fivela [START_REF] Zmarich | Consonanti scempie e geminate in italiano: studio cinematico e percettivo dell"articolazione bilabiale e lebiodentale[END_REF] by considering bilabial nasals realized in an /a/-context. One out of two subjects appeared to adhere to the Vowel-to-Vowel model, while for the other, Browman and Goldstein"s model better suited the data.

As for the geminate/singleton gesture target, in a study of bilabial plosives and fricatives Löfqvist [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF] proposed that differences in lip contact duration could originate both from the higher position of the virtual target of the geminate and from its delayed position. Given the correlation between movement displacement and velocity peak, the author tested the hypothesis that speakers could control the closure constriction duration by varying the position of the virtual consonant target. Specifically, he looked at the velocity at the closure, which is expected to be greater for higher virtual targets. However, the data on the lower lip kinematics of Swedish and Japanese speakers producing singleton and geminate consonants showed that there is no significant difference in velocity peak in long and short consonants (apart from one Swedish subject). Hence, Löfqvist [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF] concluded that subjects do not only change the virtual target position, but also vary its timing, i.e. they change the deceleration rate in order to keep the contact longer.

In this work, we will test Smith"s and Löfqvist"s hypotheses in both normal and fast speech production in Italian, as a higher speech rate often reduces the phonetic contrast of two structures in phonological opposition, and reduces the number of alternative articulatory strategies.

CORPUS AND METHOD

The corpus exploited for the investigation was composed of words and pseudo-words containing bilabial, dental and velar consonants realized as singletons (/m, l, d, g/), geminates (/mm, ll, dd, gg/) and cluster segments (/ld, dl/) in an /a/-context (e.g., "mama", "mamma", "lala", "lalla", "lalda", "ladla"); velars are not considered here. For bilabial nasals only, an /i/-to-/a/ context was also considered (e.g., "mima", "mimma"), in order to check Smith"s hypothesis on the basis of completely comparable data.

Target words were inserted in a carrier sentence, before an adverb whose first consonant was the same as the consonant in the target word (eg. "malamente" for mama, mamma, etc.: , chiama mama malamente "s/he calls mama badly").

Speakers were asked to read each sentence ten times both at a natural speech rate and, immediately afterwards, at a faster speech rate. Four speakers were recorded, but only two of them are considered in this paper: a female speaker of a north-eastern variety of Italian (NE) and a female speaker of a north-western variety (NW). The audio signal was acquired by means of a DAT recorder, while the kinematic data were collected using the 2D EMA system at the ICP lab in Grenoble. As well as the sensors used for reference (glued to the nose and the upper incisors), two were placed on the upper and lower lips, and four were glued to the midsagittal plane of the tongue in the range of about 1 cm to 5 cm from the tongue apex. The data discussed here only relate to measurements by the lower lip and tongue apex sensors for consonants, and by the tongue dorsum sensor for vowels.

Auditory test

Consonant duration is distinctive in (standard) Italian, but various dialects spoken in northern Italy do not use geminates and do not exploit the geminate/singleton contrast. First of all then, we decided to verify, by means of a perception test, whether our speakers had adequately produced geminate consonants. Secondly, we sought to look at acoustic/articulatory correlates of clear geminate vs. singleton contrasts.

A selection of the 480 stimuli produced by the two subjects was used for the perception test (for each subjects, two repetitions realized at a normal speech rate and all repetitions realized at fast rate were selected -240 in total). Five subjects from the northern part of Italy (Torino) and five subjects from the southern one (Lecce-Taranto) took part in the perception test. Using Perceval software (developed at LPL, Aix-en-Provence), subjects listened to audio files containing target words and judged whether the words included singleton or geminate consonants. At this stage, the test results were used in order to select unambiguous cases of singleton/geminate contrast. Cases in which the stimuli were wrongly recognized by at least 4 subjects during the perception test were not considered for acoustic and kinematic analysis.

The comparison of these "no contrast" cases (mainly observable at a faster speaking rate) with the "clear contrasts" was left to a follow-up study.

Measurements

The duration of the consonant and both the preceding and the following vowels was measured by manually segmenting and labelling the acoustic signal. Kinematic measurements were performed after semiautomatic segmentation and labelling of the signal [START_REF] Tisato | Recent improvements in InterFace software: New tools for Articulatory Signal Processing[END_REF]. The duration, amplitude and velocity of lower lip/tongue apex gestures (and tongue dorsum gestures for bilabials in an /i/-to-/a/ context) were calculated. For the closing gesture, for instance, the duration was calculated as the time interval between the maximum opening and the maximum closure of the articulators; the amplitude and velocity were calculated, respectively, as the vertical component of the articulator displacement and as the maximal peak on the velocity curve during the gesture.

GESTURE TEMPORAL ORGANIZATION

One-way ANOVAs were performed on the normal and fast speech rate recordings, checking whether the geminate/singleton factor was significant in relation to the vowel-consonant phasing. The results show that there are no significant differences in the time interval from the highest tongue dorsum position for [i] Thus, Smith"s hypothesis of the constant timing of maximum constriction with respect to tongue movement is not completely confirmed by our data, at least at the normal speech rate. However, the interval between the highest tongue dorsum position for [i] to the starting point of bilabial closure is significantly shorter in geminates than in singletons for both subjects at the normal speech rate Consistent results are obtained by means of analyses inspired by the recent work of Löfqvist [START_REF] Löfqvist | Interarticulator programming: Effects of closure duration on lip and tongue coordination in Japanese[END_REF]. Similarly to what happens in case of Japanese speakers, for our subjects the onset and offset of the vowel-to-vowel tongue movement occur before and after the acoustic bilabial closure respectively, for both geminates and singletons. However, only for our subjects does the beginning of the closure occur significantly earlier for geminates than for singletons (normal and fast rate for NE: [F(1,17)=17.583; p<0.05], [F(1,17)=9.804; p<0.05] respectively; NW: [F(1,16)=11.069; p<0.05], [F(1,14)=0.605; p>0.05]), while the interval from the end of bilabial closure to the end of the tongue movement does not reveal any significant difference. Thus Smith"s hypothesis concerning the anticipation of the geminate consonantal gesture in the preceding vowel and the delay in the following vowel is confirmed only for the former.

GESTURE VIRTUAL TARGET

In order to test Löfqvist"s [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF] hypothesis, the velocity peak position was checked. One-way ANOVAs were performed in order to check for the influence of the geminate/singleton factor on the magnitude of the velocity curve at the onset and offset of the acoustic closure, and on the temporal position of the velocity peak with respect to the acoustic boundaries. The results for both magnitude and position are summarized in Table 1 (upper table for the normal rate results, and lower table for the fast rate), where "Y(es)" means significant (p<0.05). For the opening gesture in alveolar consonants, the velocity curve at closure release has a significantly higher value in geminates, and its maximum peak is temporally closer to the release in geminates than in singletons (as seen for bilabials with a Swedish speaker referred to in [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF]); at the fast rate, this is true for the NE subject in all segments. In contrast, for the closing gesture at the normal rate, only few significant results are found for the two measures, and never for the same subject; at the fast rate, the results are always significant only for the NE subject. ) for both subjects. Y(es) indicates a significant (p<0.05) difference between singletons and geminates for the magnitude of the velocity curve at the onset and offset of closure (left) and for the temporal lag of its max peak with respect to the onset and offset of closure (right) in bilabial nasals and alveolar laterals and plosives.

DISCUSSION AND CONCLUSIONS

Smith"s results [START_REF] Smith | Prosodic patterns in the coordination of vowel and consonant gestures[END_REF] appear not to be completely confirmed at the normal speech rate. Our data show that the timing of maximum constriction with respect to tongue movement was not always constant in geminate\singleton consonants, and the vowel-to-vowel interval varied significantly (this tends to fit better with Browman and Goldstein"s model rather than with Öhman"s). On the other hand, Smith"s hypothesis concerning the anticipation of the geminate consonantal gesture in the preceding vowel is confirmed (consistent with Öhman"s model); however, no significant delay in the following vowel is observed. At the fast speech rate, geminates and singletons show few significant differences, limited to a single subject (NE). Thus Italian geminates appear to be best accounted for by a hybrid of Öhman"s Vowel-to-Vowel model and Browman and Goldstein"s Vowel-and-Consonant model, that is, it needs to account for the following: the variable duration of the vowel-to-vowel gesture, the only partially constant timing of maximum consonantal constriction, and the anticipation of the geminate consonantal gesture in the preceding vowel. As for the geminate/singleton gesture target, Löfqvist"s [START_REF] Löfqvist | Lip kinematics in long and short stop and fricative consonants[END_REF] initial hypothesis of a higher virtual target for geminates than for singletons is partly confirmed for the articulators considered here: At the normal rate, the hypothesis is verified in the opening gesture of alveolar consonants; at the fast rate, it verified for all types of consonants in one subject.

  (NE: [F(1,17)=4.450; p<0.05], NW: [F(1, 17)= 15.994; p<0.05]), and for neither subject at the faster rate (NE: [F(1, 17)=3.656; p>0.05], NW: [F(1, 14)=0.058; p>0.05]). In contrast, the interval between the end point of bilabial closure and the lowest tongue dorsum position for [a] is not significantly different in geminate and singleton consonants, for either subject or speech rate (normal and fast for NE: [F(1,17)=0.998; p>0.05], [F(1,17)=3.791; p>0.05] respectively; for NW: [F(1,17)=1.151; p>0.05], [F(1,14)=0.008; p>0.05]).

Table 1 :

 1 Summary of one-way ANOVAs results: Normal rate (upper table) and fast rate (lower table