• Aucun résultat trouvé

Maximum penalized likelihood estimation in a gamma-frailty model.

N/A
N/A
Protected

Academic year: 2021

Partager "Maximum penalized likelihood estimation in a gamma-frailty model."

Copied!
31
0
0

Texte intégral

(1)Maximum penalized likelihood estimation in a gamma-frailty model. Virginie Rondeau, Daniel Commenges, Pierre Joly. To cite this version: Virginie Rondeau, Daniel Commenges, Pierre Joly. Maximum penalized likelihood estimation in a gamma-frailty model.. Lifetime Data Anal, 2003, 9 (2), pp.139-53. �inserm-00138554�. HAL Id: inserm-00138554 https://www.hal.inserm.fr/inserm-00138554 Submitted on 27 Mar 2007. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) HAL author manuscript Lifetime Data Anal 06/2003; 9(2): 139-53. HAL author manuscript. Maximum penalized likelihood estimation in a gamma-frailty model Virginie Rondeau, Daniel Commenges and Pierre Joly.. inserm-00138554, version 1. INSERM Unité 330, université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux Cedex, FRANCE. The original publication is available at www.springerlink.com.

(3) HAL author manuscript inserm-00138554, version 1.      

(4)           

(5)   !#"$ %'&   . (*),+.-/),01)325476/01812:9<;>=@?A9<0B),2:C%DE6/FGFH2:0B-/2:I79<0B8KJ),2L+M+.2ON<6<C3P/Q RTSVU1WYX7Z []\_^a`_ceb dfdhgji []\_^ak cmlon ^a`_cqb p ^srm`ut l U csvfw<x,c \qy5t l.z{cMw<|<}G~<i :€‚ lƒ|_cA„ c b t U w ^ v \ w ` i†dfdhgh‡  y*t lMz{cMw<|ˆ}Š‰‹cMz{c.}ˆiŒ XŽ5S ‰ WŽ '‘’L“j”–•_—<“ ˜š™12‹IM™_9<+.2:8O›œ+M9<),CžuPAFH6h812LC,IŸ9<C3C,6j ¡›œ6/+];10B6/¢1IM2L+.£<2:8!™12LM2:+.6/-/2:0B2:)3uP¤6/+]›œ6/+ŸI.o9ˆo)3I.o)3¥¦9<Cf8B2:§¨2:01812L01¥:2 ¢¨2Lu ‹2:2L0¡6/¢1I.2:+©£/2:8¡IM;1+©£h)ž£ˆ9<C8_9ˆo9BQ ˜š™12HFG6/I©ª¥:6/FHFH6/01C3P«;1I.2:8¬2:I.M),FG9ˆo)36/0­§1+.6h¥L2:81;1+.2!),0­›œ+o9<)3C3uP FH6h8B2:C,I*),I*M™12H®‹¯ 9<C3-/6/+M)žo™1F«=¨¢1;Bªo™1)3Iª9<§1§1+.6f9<¥T™­P{),2LC,81Iª9°81)3IM¥:+.2LM2H2LI.M),FG9ˆo6/+*6<›Yo™12!81)3I.o+.),¢1;{± M),6/09ˆ018²¥:6/01I.2:³´;12L0´MC3P²816{2:I 0B6<H9<C,C36j µ81),+.2:¥L¶2:I.M),FG9ˆo)36/0·6<›7M™12°™_9<¸:9<+M8›œ;101¥mo)36/0>Qº¹¡2°I.™16j  ™16j »FG9½¼h),F¶;BF$§¾2L0_9<C3),¸:2L8KC3),¿<2LC,)3™16h6{8q2:I©o),FG9ˆM),6/0q¥¦9ˆ0Š¢¾2O9<§1§1C3),2L8o6G016/01§19<+o9<FH2LM+M)3¥e2LI.o)3FÀ9½o),6<0 6<›Ž9¥L6/0fo),0´;16<;1IO™_9ˆ¸¦9<+.8¡›œ;101¥mo),6<0¡),0¬9I.™_9<+.2:8·-f9ˆFGFG9½±Á›œ+M9<),CžuP«FG6{812:C 7)žo™¡+.),-/™f©±u¥:2L01IM6<+M2:8¡9<018 C32L›a.±so+.;101¥¦9½o2:8H8_9ˆo9BQ¹¬2V2ƒ¼B9<FG)3012šo™12#§1+.6/¢1C,2LFÂ6<›>6<¢BT9<)301),0B-ª£ˆ9<+.)Ã9<0B¥:272:I©o),FG9ˆM6/+MI›œ6/+Y+M2L-/+M2LIMI.),6/0 ¥L6h2mÄG¥L),2L0´MI:=%o™B2!›œ+M9<),CžuP«§_9<+o9ˆFG2mo2:+ª9ˆ018º¢_9<IM2LC,)3012 ™_9<¸:9<+M8­›œ;101¥mo)36/01I:Q Åh6/FH2 IM),FO;1CÃ9ˆM),6/0BIV›œ6/+*M™12 §1+.6/§¨6/IM2L8Š2:I©o),FG9ˆM),6/0q§1+.6h¥L2:81;1+.2¶9<+.2O§1+.2:I.2:0fo2L8>Q*Æǧ1+M6<IM§¨2:¥LM)3£<2¶¥:6/™B6/+.¶ÈÉJ9<³´;1),8@ʚ 7)3M™K-/+.6/;1§¨2:8 I.;1+.£{)3£ˆ9<C78_9½T9¬I.2:+©£/2:IGo6¡)3C,C3;1I.M+o9ˆM2'o™12FG2mo™16{8Ë 7™1)3¥T™Ë E9<IÀ;BIM2:8̝M6·9<019<C3P{¸:2qo™B2K+M2LCÃ9ˆM),6/0BIM™1)3§ ¢¨2Lu ‹2:2L0K2:0f£{),+.6/01FH2:0fT9ˆC>›Í9<¥LM6/+MI#9<018°M™12ª+M),I.¿'6<›812:FH2:0fM)Ã9BQ ‰ t lƒlocTnuÎ t½\ z{c \‚r c `ut<Ï(5)3+M-/)301),2*4#6<01812¦9ˆ; ÐÒÑ5Åh®†4V¯Ó#01)3h2ªÔ Õ/Õ/ÖB=×ÓV0B)3£/2L+MI.)3h25Ô (*),¥mo6/+#Åh2L-f9<C32:0«ØE6/+.812¦9<;{¼Ùh= Ú¦ÛfÜ +.;12¤Ý52LÔ 6'Åh9<),-/019ˆ¦=BÕ/Õ/ÖfÞ Ü Ø‹6/+M812:9<;h¼KDE2L812m¼¾=¨ßà47Æ5Ñ5DŽ®šQ cmáuâHw ^ xäã (5)3+M-/)301),2ˆQå476/018B2¦9<;@æ5)3IM§¨2:8>Qç;h±u¢¨6/+.812¦9<;{¼_Ù{Q盜+ ˜Ÿ2:CsQ ã ÈÉÕ<Õfʚè/è/Þ!è/Þ Û è<Õ Ú/é ß@9½¼¾Q ã ÈÍÕ/Õfʚè/è Ü Ù Û Ö!Ö/ê Ú. Ú.

(6) «ë ì´íïîO𠔈ñŸ’<ò ›œ+o9ˆ),C3uPqFH6{812:C3I:=‚¥L6/+M+.2:C,9ˆo2L8ŠIM;1+©£{)3£ˆ9<CM),FH2:IL=‚§¨2:0_9<C3),¸L2:8ŠC3),¿<2LC,)3™16h6{8>=@812LFG2L0´M)Ã9B=‚9<C,;{± FH),0´;1F«Q. HAL author manuscript inserm-00138554, version 1. Ù.

(7) ó. ô]õ'ö÷øqù­ú­û7öàü:øHõ. HAL author manuscript inserm-00138554, version 1. uÐ 0B›œ2L+M2:0B¥:2 ›œ6/+ADE6¦¼Š§1+M6/§¨6/+©o),6<0_9<CŸ™_9<¸¦9ˆ+M81I5FH6{812:CŽÈsDE6¦¼¾= Újý Þ/Ù/ʚ Ž9ˆIA812L£<2:C,6<§¾2L8þ;B01812:+Vo™12!9<IÒ± I.;1FG§ho),6<0˝o™19ˆGM™12K6<¢1IM2L+.£ˆ9ˆo)36/01IÀ9<+M2I.T9½o),I©o)3¥¦9<C3C3P·)301812L§¾2L01812:0f:=V9½ÀC32¦9<I©'¥:6<0181)3M),6/019<C,CžP·;1§¨6/0 ¥L6–£ˆ9<+.)Ã9ˆM2:ILQ‹ÿ#6j E2m£/2:+L=¨M™1),I#9<I.IM;1FH§BM),6/0qFG9jP'¢¾2A£{),6/C,9ˆo2L8>QY˜š™´;1IV)30qFÀ9<0fP°2L§1),8B2:FH),6/C36/-/),¥:9<C@I.M;18h± )32:I:=#›Í9<),C3;1+M2«o)3FG2LIq9<+M2­¥LC,;1I©o2:+.2:8 ),0fo6²-/+.6/;1§1I°I.;1¥T™ 9ˆI'›Í9<FG)3C,)32:IÀ6<+°-/2:6/-<+o9<§1™B),¥¦9ˆC*;101)žoI ã IM6/FH2 ;10BFG2:9<IM;1+.2:8«¥T™_9<+M9<¥LM2:+M)3I.M),¥:I7I.™_9<+M2L8¢fP°M™12ªFG2LF¶¢¾2L+MIš6<›Ÿo™19ˆ7¥:C3;1I.M2:+:=_I.;1¥T™Š9ˆI#-<2:012mo),¥A)30B›œ6/+.FÀ9½± M),6/0¬6/+¶¥:6<FGFH6/0¡2L0f£h)3+M6/0BFG2L0´o9<CE2ƒ¼h§¾6/I.;1+M2LI!¥:6/;1C38),0 ;12:01¥L2Ào)3FG2Ho6KM™12'I©o;181)32:8²2L£<2:0f¦QþÐu0²9 81) ‚2L+M2L0´5¥:6/0fo2ƒ¼{¦=]¥:6/+.+M2LCÃ9ˆM2:8­8_9ˆo9'FÀ9¦PK¥:6/FH2O›œ+M6<F +.2:¥:;B+M+M2L0fe2m£/2L0´MI:=Ÿ)sQç2<Q¤2L£<2:0foIA 7™1)3¥T™þ6{¥:¥L;1+ I.2L£/2L+o9<CM),FH2:I5 7)3M™1),0­M™12GIM9<FH2HI.;1¢ .2L¥Le81;1+M)301-qo™12!§¨2:+M)36h8º6<›E6/¢1I.2:+.£ˆ9ˆM),6/0‚QHÐu0º›œ+o9ˆ),C3uPKFG6{812LC,I:= 812L§¾2L01812L01¥:2«),I §1+.6h8B;1¥:2L8Ë¢fPI.™_9<+M)301-þ9<0²;1016/¢BIM2:+©£/2L8 £ˆ9<+M),9<¢1C,2H 7™1),¥T™ ),Ieo+M2:9ˆo2L8 9ˆIG9Š+M9<01816<F 2 ‚2L¥L¦=_6<+Ž›œ+o9<)3C3uPŠÈsDECÃ9¦P´o6<0>= Újý Þ<ê é ÿV6/;B-f9/9<+.8>= Újý/ý è é JŸ2Lo2L+MI.2:0>=¨Æ*018B2:+MI.2:0­9ˆ018 ª)3C,Cs= Újý/ý<Ü ÊmQ Åh2LFG) ±u§_9<+M9<FH2Lo+.),¥ª),0h›œ2:+M2L01¥:2 ›œ6/+#›œ+o9<)3C3uP«FH6h812LC,I* E9<IA)30´M+M6{81;1¥L2:8º¢fP AC,2L),0 c ` w<x 'È Újý/ý Ù/Ê#9<018 Ñ#),2:C3IM2L0 c ` w<x #È Újý/ý Ù/Êm=f9ˆ018À9ˆI†I.;1-/-/2LI.M2:8À¢fP A),C3C%È Újý êfè/ʃ=<o™B2LP!;1I.2:8G9<0À®†¯9<C,-<6/+M)žo™1F 9<§1§1C3),2L8¶o6 M™12#DE6¦¼!§_9<+©o)Ã9ˆCBC,)3¿<2LC,),™B6h6{8>QŸÿ*9<I©o)3279<018!˜š),¢1I.™1),+M9<01)]È Újý/ý Õ/ʧ1+M6<§¾6/I.2:8G9A-/2:012L+o9<C_FH6{812:C{ 7)3o™ M),FH2 £ˆ9<+©Ph)301-5¥L6h2mÄG¥L),2L0´MI†9<018!IM;1-<-/2:I©o2:8H2:I©o)3FÀ9ˆM),6/0¤o™1+.6/;1-/™!§¨2:0_9ˆC,),¸L2:8 §_9ˆ+.o),9<C{C,),¿ˆ2:C3),™16{6h8‚Q%˜š™12:+.012¦9<; 9<0B8 A+o9<F¶¢BIM¥T™­ÈÉÙ<Ö/Ö/Ö/Ê0B6<o2L8°9¤C3),01¿O¢¾2mu E2L2:0'o™B2*-f9<FHFG9A›œ+M9<),CžuP¶FH6h8B2:C¨9<018À9e§¨2:0_9<C3),¸L2:8H§_9<+.M)Ã9<C C3),¿<2LC,)3™16h6{8>Q5Ðu0­M™12!9<§1§1+.6f9<¥T™º6<›Yo™B2H§B+M2:I.2:0f¤§_9<§¨2:+L=> E2 §¨2:0_9ˆC,),¸L2Oo™B2 ™_9<¸¦9ˆ+M8­›œ;101¥mo),6<0]ÈÍIoÊ# 7™1),C32 ˜š™12L+M012:9<;Š9ˆ018 ª+M9<F¶¢1I.¥T™·ÈÉÙ<Ö/Ö/ÖfÊE§¨2:019<C,)3¸:2*M™12A›œ+o9<)3C3o)32:ILQ ˜š™12O9<),F$6ˆ›o™B2O§1+.2:IM2L0f5§_9<§¨2:+#),I7o6H§1+.6/§¾6<IM2¶9!FH2Lo™B6h8«›œ6/+7IM2:FH)ž±Á§_9<+M9<FG2mo+.),¥5)30B›œ2:+.2:01¥L2O),09 I©o+o9½o) 12:8«-f9<FHFÀ9O›œ+M9<),CžuPÀFH6h8B2:C ã 6/;B+7›œ6{¥:;BI#)3I76/0«M™12¤016/01§_9ˆ+o9<FH2LM+M),¥A2LI.M),FG9ˆo)36/0°6<›M™12ª™_9<¸:9<+M8 ›œ;10B¥Lo)36/0>=V9<018ïo™B2º9<§1§1+.6f9<¥T™ ),I'¢_9ˆIM2:8 6/0ïo™B2­§¾2L0_9<C,)3¸:2L8̛œ;1C,CVC,),¿ˆ2:C3),™16{6h8 ÈÉ9<I°6<§1§¾6<IM2:8 o6·M™12 §¨2:0_9ˆC,),¸L2:8§_9ˆ+.o),9<CEC3),¿ˆ2:C,)3™16{6h8@ʃQ¡J9<+M0B2:+È Újý<ý êfÊO§1+.6–£<2:8²o™12q¥L6/01IM)3I.M2:01¥mP²6<›VM™12q016/01§19<+o9<FH2LM+M)3¥ FG9½¼h),F¶;BFC,)3¿<2:C3),™16{6{8 2:I.M),FG9ˆo6<+†)30HM™12*I.™_9<+.2:8'-f9ˆFGFG9½±Á›œ+M9<),CžuPOFH6{812:CŸÈÍ9<018À›œ6/+Yo™B2VFH6/+M2#-/2L012:+M9<C ¥L6/+M+.2:CÃ9½o2:8¡-f9<FHFÀ9½±s›œ+o9<)3C3uPKFG6{812:CÃÊmQ­ÿ#6j E2m£/2:+L=‹M™12°;1IM;19<CE016<01§_9<+M9<FG2mo+.),¥ÀFG9½¼h),FO;1F C,),¿ˆ2:C3),™16{6h8 . . . . . .

(8) . . . Õ.

(9) HAL author manuscript. L2 I.o)3FÀ9½o),6<0eFH2LM™16h8 C32¦9<8BIo6ª9V81),I.¥:+M2mo2š81)3I.M+M),¢B;Bo)36/0O9ˆ018¶o™12š™19<¸¦9<+.8¶›œ;101¥mo),6<0¶¥¦9<0B016<¢¨2Ž812L+M)3£<2:8 ›œ+.6/F o™12'2LI.M),FG9ˆo2L8¡¥:;BF¶;1CÃ9½o)3£<2À™_9ˆ¸¦9<+.8>QŠ˜š™12q9<+©o)3¥:C,2!)3IOI.M+M;1¥mo;1+.2:8 9<IO›œ6<C,C,6j 7ILQKÐu0·I.2:¥LM),6/0 Ù{= M™12qIM™_9<+.2:8²›œ+o9<)3C3uP¬FG6{812LCŽ),I §1+.2:I.2:0fo2L8>=79<018²),0h›œ2:+M2L01¥:2q 7)3M™Ë¯K9½¼h),F¶;BF J2L0_9<C3),¸:2L8 Ý%)3¿<2:C3),™16{6{8 ®I.M),FG9ˆo)36/0¬Ès¯KJ0_Ý]®†Ê#)3IV8B2L£/2LC,6/§¨2:8K),0KI.2:¥mo),6<0ŠÕBQ7Ðu0ŠI.2:¥LM),6/0 Û  ‹2O812LIM¥L+M),¢¨2OI.),F¶;BCÃ9ˆM),6/0qI.M;181)32:I ¥L6/0181;1¥mo2L8o6G9<I.¥:2:+©T9<)30«M™12ª§1+M6<§¾2L+.o)32:I76<›o™12ª§1+.6/§¾6<IM2:8FG2mo™16{8«9<018qo6H¥:6/FH§_9<+.2ª)3šo6H9!IM2LFG) ± §_9ˆ+o9<FH2LM+M),¥†®†¯$9<C3-/6/+M)žo™1F«Q‚¹¬2Ž™_9¦£/2Ž9<C,I.6*§¨2:+.›œ6<+MFH2:8OI.),F¶;BCÃ9ˆM),6/01I%M6*),C3C,;1I©o+M9ˆo2o™B2E2:I©o)3FÀ9ˆM),6/0¤6<› M™12*™_9ˆ¸¦9<+.8À›œ;101¥mo),6<0>QàÐu0°IM2L¥LM),6/0q誝o™12VFG2mo™16{8'),I‹9<§1§BC,),2L8GM6 9OI.M;18BPG6<›>M™1252 ¾2:¥mš6<›]9ˆC,;1FH),0´;1F 6/0·M™12'+.),IM¿þ6<›#812LFG2L0´M)Ã9K)30²9ŠCÃ9<+.-/2À¥L6/™16/+©«ÈÍI.2:2qÝ%2LM2:010B2:;1+ c ` w<x ,= Újý<ý<Û Ê¤§¨6/I.IM),¢BC3P¬§1+M2LIM2:0fM),01)30´M+o9½±Á-/+M6<;1§°¥:6/+.+M2LCÃ9ˆM),6/01ILQ . inserm-00138554, version 1. . O÷ 5ù. . (*),+. . . . f÷ ¶ü mö. . ! ". $# &%. øqù . '#. -/.1032465'087. ¬¹ 2«¥L6/01I.),812L+GFH6h8B2:C,I )30 7™1),¥T™ o™12q™_9<¸:9<+M8²›œ;101¥mo)36/0˧19<+.MC3P·8B2:§¨2:0181IG6/0Ë9<0Ë;B016/¢1I.2:+.£ˆ9<¢BC,2 +M9<01816/F

(10) £ˆ9<+.)Ã9<¢1C32Ao™16/;B-/™f*o6À9<¥L*F¶;1Cžo),§BC,),¥:9ˆo)ž£/2LC3PG6/0Ko™B2¶™_9<¸:9<+M8>=¨IM6Go™_9ˆ59ÀCÃ9ˆ+M-/2A£ˆ9<C,;B2O6<›àM™12 £ˆ9<+.)Ã9<¢1C32e)301¥:+.2¦9<I.2:IAo™B2 ™_9<¸¦9ˆ+M8>Qª¹¡2¶M+M2:9ˆAo™12 ¥:9<IM2 6ˆ›‹+.),-/™f©±u¥:2L01IM6<+M2:8þ9<0B8þC32L›a©±Áo+.;101¥:9ˆo2L8­8_9ˆT9h= 9<0B8K9<C3C,6j  ›œ6/+7I.M+o9ˆM;1F!±ÁIM§¨2:¥L) _¥ª¢_9<I.2:C3),012ª™_9<¸:9<+M8BI:Q‹ß@6<+7M™12 qÈ Ú Êš)30181)ž£h)381;_9<C‚6<›M™12 ¤I.o+M9ˆo;BF È Ú ÊŽ9<018°M™12 O-<+M6/;1§¬È Ú Êm=BC32L 812L016<o2AM™12ªIM;1+©£h)ž£ˆ9<C>o)3FG2LI ;10B812:+5I©o;18hP­9<018­C32L ¢¨2OM™12¶¥:6<+M+M2LIM§¨6/0181)301-°+M)3-/™f.±Á¥:2:0BIM6/+.),01-Ho),FH2:ILQ5˜š™12 6/¢BIM2:+©£ˆ9ˆo)36/01IA9<+.2 FG)30%È ÊO9<018·M™12°¥:2L01IM6<+M),0B-­),0181)3¥¦9ˆM6/+MI mQ¬˜š™12°I.;1+.£{)ž£<9ˆCEo)3FG2LI FG9¦P¢¾2qC32L›a.±so+.;101¥¦9½o2:8 ã 6<01C3PI.;1¢ .2L¥LoIH 7)3M™ 9<+M2q6/¢1I.2:+©£/2:8 é  ‹2K9<I.IM;1FH2°o™_9½HM™12 C32L›a.±so+.;101¥¦9½o),6<0Ào)3FG2LI 9<+.2ª),01812L§¾2L01812L0´V6<›Ÿo™12ªI.;1+.£{)3£ˆ9<C>M),FH2:I Q ;1+š›œ+o9<)3C3uPHFH6h812LC>IM§¨2:¥L) _2LI#M™_9ˆšM™12ª™_9<¸¦9ˆ+M8q›œ;101¥LM),6/0q¥L6/0181)žo),6<0_9<C‚6<0«M™12A›œ+o9<)3C3uPG),I ã . G ;>=. G. ?. E. ?. =RQ. LO. E. =RQ. JK;>=. <A$BBBAIH. 1S. T. :9<;>=. A S. E. E. VU E. =RQ. h. PO. <A$BBBAIN. E. <A$BBBADCFE. =. =RQ. =RQ. . k. LJM?. 9@?. E. eO. E. E. =RQgfih. ?XWZY\[]_^L`Iacb<]_^L`Dd. =RQ. =,Q. jO. =RQ. E. =RQ. . l E. =RQ. È Ê LmZnpo. E "?qo. E l!r. È .ÊB2m¼h§ŸÈ sm =. Û. \tvuxw E. =,Q. Ê. ÈÚÊ.

(11)  7™12L+M2 È .ʎ),IEM™12ª¢_9<I.2:C,)3012A™_9<¸:9<+M8q›œ;101¥mo)36/0'›œ6/+šI.M+o9ˆM;1F é È Ê 8B2:016<M2:I M™12Y¥:6j£ˆ9<+M),9ˆo2à£<2:¥LM6/+%›œ6/+>o™B2 †),0181)ž£{),81;_9ˆC<6<›BI.o+M9ˆo;BF 9<0B8e-/+.6/;1§ M=ˆ9<018 À)3I%o™12Y¥:6<+M+M2LIM§¨6/0181)301£<2:¥LM6/+76<›+M2:-<+M2:I.IM)36/0§19<+o9<FH2LM2:+.I:Q DE6/018B)3o)36/0_9<C3C3PK6/0·o™12H›œ+o9<)3C3uP =M™12À›Í9<)3C,;1+.2 o),FH2:I 9<+M2À9<IMI.;1FG2L8·o6Š¢¨2 )301812:§¨2:0B812:0f¦QYÐÁ7)3Iš9<IMI.;1FH2:8°o™_9½šo™12 I79<+M2A)301812L§¾2L01812:0fMC3P°9ˆ018q),812L0´M),¥:9<C,CžPG8B),I.M+M)3¢1;Bo2L8'›œ+M6/F 9A-f9<FHFG9*81),I©o+.),¢1;BM),6/0e 7)3o™!FH2¦9<0 Ú 9<018!;10B¿{0B6– 70H£ˆ9<+M),9<01¥:2 é o™127§1+.6/¢_9<¢1)3C,)žuPe8B2:01I.)3uP¶›œ;10B¥Lo)36/0 )3IŽo™´;1I ã 2m¼h§ È fÊ ‹È Ú <Ê Ý]9<+M-<2e£ˆ9<C,;B2:I#6<› GI.),-/0B)3›aP«9À¥LC,6/I.2:+#§¾6/I.)3M)3£/2¤+M2LCÃ9ˆM),6/0BIM™1)3§¢¨2Lu ‹2:2L0ºM™12OI.;1¢ .2L¥LoIA6ˆ›o™12eIo9<FH2 -/+.6/;1§º9<0B8­-/+M2:9ˆo2L+A™12LM2:+M6<-/2:012L)3uPŠ9<FG6<01-'o™12O-/+M6/;B§1I:QeÆ*IA81)3IM¥:;BIMIM2L8¬¢fPŠÑV),2LC,I.2:0 c ` w<x °È Újý<ý Ù/Êm=  ‹2*9ˆIMIM;BFG2šo™B2V¥L2:01I.6/+M)301-¤M),FH2:I M6ª¢¾2#),018B2:§¨2:01812L0fE6<›¨o™B2#›Í9<)3C,;1+.2Eo)3FG2LIY9<018H6<›‚M™12š›œ+o9<)3C3M),2:I Q lyr. G. Lm. =. w. E. G. =RQ. M9<;>=. o. ~o. sw

(12) z E. ~J. ~O. E. ?. E. =. z A O. E. A$BBBA O. =€. =RQ. A{BBBA w}| E. =RQ. u. t. E. =‚. ]_^. E„ƒ. HAL author manuscript. 6 . \‡ ?. †. ‡ˆ. zK‰„ŠŒ‹yzK –. &Ž‘‡“’” •. ’” , . zK‰„Š.  . . inserm-00138554, version 1. S. o. E. =RQ. E. (*)—(. ˜™1š‚0œ›y08™1v0ŸžR™¡ y.103¢£.1¤"›y0¥5§¦¨¤2©2©¤8ª«š‚›y¤žR7— ”¬­2©465'0¥7. š˜ ™12¤),812:9 6<›M™12eDE6¦¼«§_9<+.M)Ã9<C¾C,)3¿<2:C3),™16{6{8'816{2:I7016<7¥:9<+M+©P°6j£/2:+#),0«9 IM)3FG§BC,2AFG9<01012L+:=1I.),01¥L2ªM™12 )30´M2:-/+M9ˆo)36/0°6j£/2L+#›œ+M9<),Cžo),2LIE)30181;1¥L2:IV9!¥L6/FH§1C,)3¥¦9ˆM2:8'›œ6/+.F ›œ6/+Žo™B),I7C,)3¿<2:C3),™16{6{8>QÐu01I©o2:9<8>=_ E2ª;1I.2¤M™12 ›œ;1C3CC,)3¿<2:C3),™16{6{8>QGÐu0¬o™12H-f9<FHFÀ9–±Á›œ+o9ˆ),C3uP«FH6h8B2:Cs=9¥L6/FH§_9<¥Lª›œ6/+.F¶;1C,9q›œ6/+AM™12G›œ;1C3CC,)3¿<2:C3),™16{6{8­¥¦9<0 ¢¨2À6/¢hT9<)3012:8¬¢´P¬),0fM2:-/+M9ˆo)301-6<;BeM™12G›œ+M9<),CžuP ›œ+M6<F M™12 .6<),0fOC3),¿ˆ2:C,)3™16{6h8 È ªC32:)30 c ` w<x ,= Újý/ý Ù é Ñ#),2:C3IM2L0 c ` w<x ,= Újý<ý Ù/ÊmQŽß@6<+7M+M2:9ˆo)301-GC32L›a©±Áo+.;101¥:9ˆo)36/0° E2eF¶;1I.V 7+M)žo2¤9GC3),¿<2LC,)3™16h6{8°¥:6<0181)3M),6/019<C%6/0 Q˜š™1),I)3Ià6/¢Bo9<),012L8!¢´PO81)3£{)381),01-*¢´POo™127C,)3¿<2LC,),™B6h6{8e6ˆ› Ȝ›œ6<+ Ú !é ʃQ5¯6<+M2:6j£<2:+:=¾ E2¶¥:9<0­9¦£/6<),8K;BIM),0B-'-f9<FHFÀ9¶›œ;10B¥Lo)36/01IV),0M™12O2ƒ¼h§1+M2LIMIM)36/0­6<› Ú ·é Ú M™12EC36/-ˆ±uC3),¿ˆ2:C,)3™16{6h8>=Lo™´;1IàFG9<¿´),01-V)32¦9<I.),2L+o6V¥:6/FH§1;BM2<Qà˜š™12‹›œ;1C,C´C,6<-ˆ±uC3),¿<2LC,)3™16h6{8*›œ6/+C,2m›a.±ÁM+M;10B¥¦9ˆM2:8 8_9½T9 ¥:9<0qo™12L0¢¨2A 7+M)3.o2L0 ã O. o. E. =RQ®f¯h. <A{BBBADH. E. . E. FO. =RQ. 9 ?. \. <A$BBBADC°E. =. è. E. =RQ®f¯h. E. =RQ. J8?. <A$BBBAIN. G. ?.

(13) ±. È È Ê /Ê lyr. A t. B. ¶¸· ³ ². A "?. Eµ´. ³ z. ³ ´ =. OÈ Ú . z. ’” . U E z ´ Q. HAL author manuscript. º. inserm-00138554, version 1.  7)žo™ È Ê È :È Ê. ]Æ´ Å rRd. W YKÄ. ³Ç zZÈ ´. ³ z ´. ³ =. r Q. z ´. ¿. C30%È Ú 1È . º. z ´. E ». r Q. =. KT. =. KT =. z&¿ ´. E. =RQ. E. \tvu¾w. =RQ. È ÊB2ƒ¼h§ŸÈ E. h. ÈÉÙ/Ê. ‚•. È ÊB2m¼h§ŸÈ. ]¾^ . ³. ]¾^ . ³ =. ] Ä. º. . lyr. =RQMº. º. ·. ÂÁ. E. ·. ½¼. Ú C,0 Ú º. Ž¹tvu_w. =,Q. ÊBC30 Ú E. ºe». ’« . C,0>È È ÊMÊ. ]_^ . \tvu_w. =RQ. E. E. =,Q. Ê. „À. Ê. RÃ. =RQ. 1ÊMÊ. ÊÉ. —ËDÌ. È Ê.Ê é È ÊH9ˆ+M2qo™12«¥:;1FO;1CÃ9ˆM)3£<2«¢19<IM2LC,),0B2™_9ˆ¸¦9<+.8˛œ;101¥mo)36/01IH9<018 Ž),I‹o™12A0´;1F¶¢¨2:+š6ˆ›6<¢1IM2L+.£/2L82m£/2L0´MIV)30'o™12 ª-/+M6/;B§>QÐÁ›à9¶§19<+o9<FH2LM+M)3¥ ¢_9ˆIM2:C3),012G™_9<¸:9<+M8·›œ;10B¥Lo)36/0·)3I¶IM§¨2:¥L) _2L8>=o™12L0FÀ9½¼h)3F¶;1F C,)3¿<2LC,),™B6h6{8¬2LI.M),FG9ˆo2LI 9<+M2À9¦£<9ˆ),CÃ9ˆ¢1C,2H¢fP 81)3+M2L¥LoCžP'FG9½¼h),FH),¸L),01-'ÈsÙ/ÊAȜIM2:2eDE6/I©o)3-f9<0«9<018 AC,2:)30>= Ú¦ý/ý ÕfʃQ l!r. ». E. lyr z. B

(14) ?. ·. ?qÍ. =. ´. . Í. z. Q. ]¾^. ´. A$BBBA lyr. B. z W$YÆÎ ]¾^L` ´. ·. B. r. u. ¿. B. =. z d. 'J\;>=. . . Ï. Aõ ¦ü Aù ¦ü :ü Šø°øqù. . н. V# {Ñ:. ­÷ø ¶û. # $Ò@'# $. Ð Ð. . j. ¬¹ 2À),0fM+M6{81;1¥:2À9I.2:FH)ž±u§19<+o9<FH2LM+M)3¥!9<§1§1+.6f9<¥T™·o6 .6/),0fMC3Pº2:I©o)3FÀ9ˆM2 o™12'§19<+o9<FH2LM2:+.I Y= «9<018 M™12G¢19<IM2LC,),0B2H™19<¸¦9<+.8¡›œ;101¥mo)36/0 È .Êm= 7™B),¥T™¡)3IO9ˆIMIM;BFG2L8¡o6«¢¾2HIMFH6{6<o™>QÀÆ §¨6/IMI.),¢1C32!FG2:9<01Iª›œ6/+ )30´M+M6{81;1¥L),01-IM;1¥T™ 9<0 wÀΨl ^st l ^¿{0B6– 7C32:81-<2'),I¤o6Š§¨2:0_9ˆC,),¸L2GM™12'C,)3¿<2LC,),™B6h6{8º¢´P¡9M2:+MF  7™1)3¥T™™_9<I C,9<+M-/2A£ˆ9<C3;12:I7›œ6/+#+M6/;1-<™›œ;101¥mo)36/01IOÈ Å{;1C,C3)3£ˆ9<0>= Ú¦ý ê/ê é N<6/C3P<=¾DE6/FGFH2:0B-/2:IV9<018KÝ]2mo2L01012:;B+:= Újý<ý êfÊmQ ˜š™´;1Iª›œ6/+5o™B2H£<2:¥LM6/+¤6<›E¢19<IM2LC,),0B2 ™_9<¸¦9ˆ+M8º›œ;101¥LM),6/0BI:= È Ê È :È Ê È ÊMÊ =% E2H812 1012HM™12 FG9½¼h),F¶;BF §¨2:0_9ˆC,),¸L2:8qC,)3¿<2LC,),™B6h6{8À2LI.o)3FÀ9½o6/+.I¤Ès¯KJ0_Ý]®†ÊŽ6<› È .ʃ= ·9<0B8 !9<I7FG9½¼h),FH),¸L),01- ã @. }t. " . lyr sm. k. ƒ. l!r. B '?. lyr Lm. Ó. ±. È È Ê /Ê È È Ê /Ê lyr. B. A t. A "?. ±. l!r. B. A t. A 8. · ³ =. ´. z°Ô. =MÕ¯ r Ö. lyr z. A{BBBA l!r. B. yt. ·. B. . u.  . È .Ê. ÈÍÕfÊ. ly×r × € sm ,Ø<m =.  7™12L+M2 È È Ê /ÊA),Iªo™12G›œ;1C,CYC,6<-ˆ±uC3),¿<2LC,)3™16h6{8Š812 _012L8 )30ïÈÉÙ/Êm=9ˆ018 ÖB=šÈ Ú Êe9<+.2 §¨6/IM)žo)ž£/2ÀI.FG6{6<M™1),01-K§_9<+o9ˆFG2mo2:+.IO›œ6/+¶2:9<¥T™²I.M+o9ˆM;1FQºÐu0²§1+M9<¥LM),¥:2ˆ=o™12'+M9<01-/2°6ˆ›#M™12')30´M2:-/+M9<CE)3I ±. l!r. B. A t. A . . Ü. Ô. = Ù. G. ?. ”A$BBBAIH.

(15) +.2:I.M+M)3¥Lo2L8«M6 o™12ª§¨2:+M)36h8° 7™12L0Š9ˆ7C32¦9<I©#6/012ªIM;1¢ .2:¥LV),IšI©o)3C,C%9ˆ7+.),I.¿¨QY˜š™1)3I72m¼h§1+M2LIMI.),6/0+M2:§B+M2:I.2:0foI 9eM+o9<8B2m±u6 K¢¨2Lu ‹2:2L0«›Í9<)žo™B›œ;BC,012LIMIEM6Oo™12*8_9ˆT9h=19<IŽ+.2:§1+.2:I.2:0fo2L8K¢fP È Êƒ=_9<018 .I.FG6{6<M™1012:I.I 6<›%M™12 I.6/C,;BM),6/0‚=f9<I+M2L§1+M2LIM2L0´M2:8'¢fP¶M™127IM³´;_9<+.2:8H016/+.F 6<›¨o™127I.2:¥:6<018G8B2:+M)ž£ˆ9ˆo)ž£/2<Qàß@6<+àCÃ9<+.-/2 =/o™B27M2:+.F È .Ê E 7)3C,C>¢¨2A›œ6/+M¥L2:8M6j Ž9<+.8K¸L2:+M6À9<018qo™12¤¥:;B+.£/2LI È ÊE 7),C3C%9<§1§1+.6f9<¥T™C,),0B2¦9<+Ž›œ;10B¥Lo)36/01I76<› M),FH2<QŸÐÁ› ),IàI.FÀ9ˆC,Cs=–o™B2:0 o™12šFG9<)30¶¥:6/0fM+M),¢B;Bo)36/0¶o6 È Ê 7)3C,C{¢¾2ŽM™12šC,6/-½±uC,)3¿<2LC,),™B6h6{8 È È Ê <Ê 9<0B8qM™12ª¥:;1+©£/2¤2:I©o),FG9ˆM2  7),C,C¨o+M9<¥T¿Ào™B2¤819ˆT9 ¥:C36/IM2LC3P<=_¢1;Bš 7),C3C>¢¨2¤FH6/+.25),+.+M2:-<;1CÃ9<+LQ . ±. «. B. eÚ. ŒÛ. =. Ô. Ü. l. ×r × € sm ,Ø<m =. Þly Ý ß. HAL author manuscript. l!r. àP),+. ±. Ó. =. Ô. =. B. ±. B. lyr. B. A t. A . =. á‘â'7Rž,™10㪔ä1¤"¢£0œ5§¤â'â1›y4œå1žR2¤M yžæ4j™1¢. inserm-00138554, version 1. ¹ ™12L0·o™12'§¨2:019<C,)3¸:2:8¡C,),¿ˆ2:C3),™16{6h8º)3IO;1I.2:8o6Š2LI.M),FG9ˆo2G016/01§_9ˆ+o9<FH2LM+M),¥H+M2L-/+M2LIMI.),6/0·›œ;10B¥Lo)36/01IL= )ž!¥¦9<0 ¢¾2qI.™16j 70 o™_9½ o™12«2:I©o),FG9ˆM6/+MI!9<+.2q¥:;1¢1)3¥qIM§1C3),012LI! 7)žo™ ¿´016<oIH9ˆH2m£/2:+©P 6/¢1IM2L+.£<2:8Ì8_9½T9 §¨6/),0f'ÈÍI.2:2qÅh)3C3£<2:+MFG9<0 È Újý êfè/ÊMʃQÐu0¬o™12G§1+M2LIM2:0f!¥L6/0fo2m¼{ 6ˆ›7™_9<¸¦9ˆ+M8¡›œ;10B¥Lo)36/0¡2LI.M),FG9ˆo)36/0>=]o™12L+M2 )3I 016¡I.;1¥T™ I.),FH§1C,) _¥¦9ˆM),6/0‚Q®¼19ˆ¥LG¥:6/FH§1;Bo9ˆo)36/0²6<›*M™12:I.22LI.o)3FÀ9½o6/+.I ),I!016<H§¨6/IMI.),¢1C329ˆ018 M™12 ¯KJ0_Ý]® 6ˆ› È .Ê'F¶;BI.q¢¨2¬9ˆ§1§1+M6¦¼h),FG9ˆM2:8 ;1IM)301-²IM§1C3),012LI:QµÅ{§1C,)3012:Iq9<+.2º§¾6/CžP{016/FH)Ã9<C7›œ;101¥mo),6<01I  7™1)3¥T™·9<+.2!¥:6/F¶¢B),012L8¬C3),012:9<+MCžPKo6«-/)ž£/2 È Ê È Êm=] 7™12:+.2Go™B2 È Ê¤9ˆ+M2!¥:;1¢B),¥À¯q± I.§1C,)3012:IL=†)ÉQ×2ˆQ·IM§BC,),0B2:I 6<›V6/+M8B2:+ Û ÈÉ4#9<FGIM9¦P/= Újý ê/ê/ÊmQ·Ø†P81),+.2:¥m!),0fo2L-/+o9ˆM),6/0²9ˆ018 7)3o™M™12qIo9<FH2 £<2:¥LM6/+E6ˆ›>¥:6{2LÄH¥L),2:0fMI È Ê =´)3†),I†9<C3IM6¤§¾6/I.IM)3¢1C,27o6¤6/¢Bo9<),0!o™12#¥:;BF¶;1CÃ9½o)3£<27),0fo2L01IM)žuP ›œ;10B¥Lo)36/0 ã È Ê È Ê# 7™12:+.2 È Ê#9<+M2OÐs±uIM§BC,),0B2:I5812 _012L8¬9ˆI È ¾Ê È ¾Ê ]Q5Ðu0 6/;B+59<§1§B+M6f9<¥T™‚=>9<Cžo™16/;B-/™M™12:+.2 9<+M2e81) ¾2:+.2:0fAI©o+o9½T9B=@ E2O;1IM2¶M™12OIM9<FG2e¢_9<I.),I*6ˆ›YIM§1C3),012LIV›œ6/+V2¦9<¥T™ I©o+o9½o;1F«=1IM6H6/01CžPÀM™12ª¥:6{2LÄH¥:)32:0foI 9<+.2A81) ¾2:+.2:0f7›œ6/+Žo™12ª81)3I.M),01¥m7I.o+M9ˆT9hQ ÑV6ˆo2GM™_9ˆeo™12'2LI.M),FG9ˆo6/+¤),Iªo™B2q¯KJ0_Ý]® È Êm=à 7™B),C,2 È Ê¤),IO9<09<§B§1+M6¦¼h),FG9ˆo)36/0ºo6KM™12À2LI©± M),FG9ˆo6/+ È ÊƒQ°˜š™12'9<§B§1+M6¦¼h),FG9ˆo)36/0º2:+.+M6/+¤¥¦9<0¬¢¾2HFG9<812G9<IeI.FÀ9ˆC,CY9<I¤812:I.),+.2:8·¢fPþ),01¥L+M2:9<IM)301-«M™12 0´;1F¶¢¨2:+76<›¿´016<MI:Q . lyr Lm. ! çl r. é =. r. ç. ¿. =. B :?ëÍ. Ä. E>´. ?. é = z A$BBBA é = Ä. z éç E W E =. =. Eµ´. z. é ç = ELêgE. B. êgE. B. u. @W E. B. Ä. B ?èÍ. . B. 1W E sì. 6?. Üí r. êgE \î. ,ؓî. . . é = E. §l Ý. lÝ. àP)—(. B. Âçl. B. B. ïg¤"›!žR¤™1v034¨šð y.10Ÿ0œ¢ ñž,2¤M ñ0œ¢. ¬¹ 281+M2m ·6/;1+‚),01I.§1),+M9ˆo)36/0*›œ+M6<F A+o9¦P I% ‹6/+M¿¶È A+o9¦P/= Újý<ý Ù é ª+M9jP<= Újý/ý<Û ÊƒQ%˜67I.),FH§1C,)ž›aPV0B6<T9ˆM),6/0BI  ‹2¶ 7),C3C¥L6/01IM)3812:+*6/01C3P«o™B2 ;101I.M+o9ˆM) _2L8­¥¦9<I.2<Q¤¹¡2¶FG9<¿ˆ2¶o™12 9ˆIMIM;BFG§BM),6/0ŠM™_9ˆ È ÊV¢¨2:C36/01-/IVo6 Þ ò. ƒ. . Æ. . lyr. B.

(16) M™12KI.§_9<¥:2K-/2:012L+o9ˆM2:8ï¢fP IM§1C3),012LI:=šIM6¬o™12FG6{812:C#),IHIM§¨2:¥L) _2L8ï¢fPÌ9þ§_9<+o9ˆFG2mo2:+H£/2L¥Lo6<+ È é é /ʎ 7™12L+M2 À¢¨2:C36/01-/I7o6À9ÀIM;B¢1IM§_9ˆ¥:2 Ð 4 Q7Ðu0Ko™B2O-/2L012:+M9<C¥:9<IM2¤o™1)3I )3Iš6/01C3P'9<0«9<§1§1+.6¦¼B)3FÀ9½o),6<0>Qà˜š™12ª§¨2:0_9<C3),¸L2:8qC,6/-½±uC,)3¿<2LC,),™B6h6{8!¥¦9<0qo™12L0K¢¨25 7+M)žMo2L0K9ˆI ã . ». tãz A$BBBA t“|. é uô A$BBBA é õ u. . @ó.

(17) ó u. ± Ó. È È Ê Ê È {Ê lyr. A t. B. z. ø. È {Ê. ± Kó 8úù. "?. |. ·"ø. ö÷. ?. Kó. HAL author manuscript. ². inserm-00138554, version 1.  7™12L+M2 È {ʃ=@M™12O§¨2:019<C,)3¸¦9ˆM),6/0°o2L+MF«=¾8B2:§¨2:0181I*6/0M™12O0´;1F¶¢¨2:+V6<›Y-/+.6/;1§1I 9ˆ018Š6/0 '¢1;B50B6< 6/0­M™12G819ˆT9BQ È {Ê*FG9¦P­¢¾2H9' ‹2:),-<™´M2:8¬IM;1F 6<›‹IM³´;_9ˆ+M2:8¬016/+.FGIª6<›‹IM2L¥:6/018¬812:+.)3£ˆ9ˆM)3£/2LIª6<›‹M™12 È ÊŽ9<I7),0¬ÈÍÕfÊm=1¢B;B7o™12Ao™B2:6/+©Pq9<§1§1C3),2LIŽo6!6<o™B2:+7¥T™16/)3¥:2:I76<›§¾2L0_9<C3),¸¦9½o),6<0>Q ¹¬2‹¥:9<0¶IM™B6– M™_9ˆŸo™12Ž¯KJ0_Ý]® 59<I.P{FH§Bo6ˆo),¥:9<C,CžP*›œ6/C3C,6j 7IŸ9VF¶;BC3o)ž£ˆ9<+M),9ˆo2016/+MFG9<C´81)3I.o+.),¢1;ho),6<0  7)žo™qFG2:9<0 @ù. Kó. ûó. N. ². ù. Kó. ². lyr. B. óÝ. ÀÈ ´Ê ü. ó Ý "?qó r. C,),F . ‹yz. £ˆ9<+jÈ ´Ê. ‹yz. ”ó Ý ¨?. ù. Kó r yÿ. ÈÛ Ê. Kó r. ó ². ². ²yý. 9<0B8q£ˆ9<+.)Ã9<0B¥:2m±Á¥:6j£ˆ9<+M),9<01¥L2AFÀ9ˆM+M) ¼. È Ê  È Ê. ÖÞþ. È Êu£<9ˆ+ \ó r. ±. ‘ÿ ó. È Ê. È Ê. ‹yz. Kó r. ². ÈÉè/Ê. Kó r. ². þ. þ.  7™12L+M2 È Ê È Ê   È ÊŽ9<018 È Ê   È Êm=_9<0B8 )3IŽo™12Ao+.;12A£ˆ9<C,;12A6ˆ› _Q ÐÁ7›œ6/C,C36j 7IE›œ+M6/FÈ Û Ê‹M™_9ˆV 9

(18)  012:¥L2:I.Io9<+©P¥L6/0181)žo)36/0'›œ 6/

(19) +š ¥:6<01IM)3I.o2L01¥LPq)3I Kó r ?. Kó r. W. ². Kó r. º. \ó r ?Ÿ. W. ². Kó r. ûó r. ó. ². þ. C,)3F ²yý. ‹yz. È Ê  È Ê Ö ù. Kó r yÿ. ó ². Kó r. ?. ² Öþ. 6/+L=f;101812L+E9ª¥:6<0181)3M),6/0!6<›¾I.M2¦9<8hP!),01¥L+M2¦9ˆIM2#6<›>)30B›œ6/+MFG9ˆM),6/0¤ 7)3o™ ÂÈ È Ê  ´È ÊMÊ ã   È Ê 

(20) È .Ê ƒ=>o™1)3IA¥:6/018B)3o)36/0­),I*2:³´;1)3£ˆ9<C32:0fAo6  ´È ÊmQOÐÁ›  {È ÊƒQO¹¬2 ¥:6/0 .2L¥LM;1+M2 M™_9ˆšo™B),Iš),I79ˆC,IM6H9 IM;hÄG¥L),2L0´V¥:6<0181)3M),6/0‚Q ˜Ž ‹6G2LI.o)3FÀ9½o6/+.IšFÀ9¦P'¢¨2ª§1+M6<§¾6/I.2:8q›œ6/+Ž£ˆ9<+jÈ ´ÊmQ \ó r ¨?. |. . N. *ù. Ü. ². ?. Ô. ². *|. Kó r ¨?. N. ². l. r. ×r × € Lm RØ<m. ?. þ. Ô. Ö. ”ó Ý. ê. ². |. N. .

(21) ÐÁ›šM™12À8B),I.M+M)3¢1;Bo)36/0¡6ˆ›šo™12G6/¢1IM2L+.£ˆ9ˆM),6/01IO¢¾2LC,6/01-<I¤M6Ko™12À¥:CÃ9ˆIMIO6ˆ›7FG6{812:C3Ie¥L6/01I.),812L+M2:8‚=Y ‹2 ™19j£<2A£<9ˆ+   È {Ê È {ʎ9<018q¢fPqIM;B¢1I.M)3o;ho),0B- H),0þÈÉè/ÊE E2ª6/¢Bo9<),0 ã 

(22) . Kó ?. W. Kó. óÝ. ².   . :È ´Ê z. ó Ý "?. ‹yz Ý. È ´Ê È ´Ê óÝ. WÝ. óÝ. ² ². È ´Ê. ‹yz Ý. ÈÜ Ê. óÝ. ². þ. þ. HAL author manuscript.  7)žo™ È ´Ê    È ´Ê Ÿ9<018 È ´Ê   È ´Ê sQ 

(23)  

(24)  Åh;1C3C,)ž£<9ˆ0  Æ»£ˆ9<+M),9<01¥L2¤2LI.M),FG9ˆo6/+7812L81;1¥L2:8Š›œ+M6<F

(25) 9G¢_9¦P<2:IM),9<0­9<§B§1+M6f9ˆ¥T™ E9<I*§1+.6/§¨6/IM2L8Š¢fP È Újý ê/ê/ʎ›œ6<+V9HIM)3FG)3CÃ9<+Ž§B+M6/¢1C32:F«Q Ðu0KM™1),IV9<§1§B+M6f9<¥T™ '),I7¥:6<01IM)3812:+.2:8­9<I*9G+M9<01816/F$£ˆ9<+.)Ã9<¢BC,2<Q Ó#§¡o6K9¥L6/01I.o9<0f¦=àM™12À§¨2:0_9ˆC3uPºo2L+MF ),I¤+M2L-f9<+M8B2:89<I¤o™12G§1+M)36/+¤C,6/-ˆ±ÁC,)3¿<2:C3),™16{6{8K›œ6/+ Š9<018 M™12!§¾2L0_9<C3),¸:2L8ºC,6/-ˆ±ÁC,)3¿<2:C3),™16{6{89ˆIªM™12!§¾6<I.o2L+M)36/+AC,6/-½±uC,)3¿<2LC,),™B6h6{8>QªÆV›aM2:+ªIM6/FH2 FG9<01),§B;1CÃ9ˆM),6/0  ‹2¶6/¢hT9<)30­9ÀF¶;1Cžo)ž£<9ˆ+M)Ã9½o2ª-f9<;1I.IM),9<0­9<§1§B+M6¦¼h),FG9ˆo)36/0K81)3I.M+M),¢B;Bo)36/0«›œ6<+ q9<018ŠM™1),IVFÀ9<¿ˆ2:IA)ž §¨6/I.IM),¢BC,2*M6G;1I.2 È ´ÊŽI.),FH§1C3PÀ9<I79 £<9ˆ+M)Ã9ˆ01¥:2A2LI.o)3FÀ9½o6/+LQ ˜š™12LIM2O2LI.M),FG9ˆo6/+.IŽ›œ6/+š£ˆ9<+¦È {ʚ8B6G016ˆ#o9<¿<2¤),0fM6G9ˆ¥:¥:6<;10fVM™12A£<9ˆ+M)Ã9ˆ¢1),C3)3uPH81;12ªo6!o™12¤¥T™16/)3¥:2ª6<› M™12ªIMFH6h6<M™1),0B-¶§_9<+M9<FG2mo2L+MI:Q WÝ. ó Ý ?. . ó Ý —Ë. ó Ý ?. Ý. È. ². |. . ó Ý —Ë. È. ². þ. k. ƒ. ûó. }ó. inserm-00138554, version 1. 1ó. ‹yz. Ý. ”ó Ý. ². þ. óÝ. àP)„à. . !. ½4j™. 5'0¥™1v0Ÿä1¤™15'¢. ß_+M6/F È Ê È Êà E2V812:8B;1¥:2*M™_9ˆ‹£<9ˆ+¦È È .ÊMÊ  7)3IM2 ý &è %µ¥:6/0 1812:01¥L2e¢19<0181IV9<+M2A6ˆ›M™12A›œ6/+MF y çl r. B ?qÍ. =. Ä. E>´. z é ç EsêgE =. ! çl r. B. =. sm. #". ?. u. È “ Ê £ˆ9<+jÈ Ê $" È “ Êm={IM6¶§¨6/),0f©± È. é Ý = —Ë. £. ! çl r. È .Ê(' Ú åý<Ü*) sm =. <B. " u. È “ Ê ,£ˆ+ 9<+jÈ Ê -" È “ Ê é Ý = æË. È.  7™12L+M2." È “ Ê È mÈ .Ê È .ÊMÊe)3IeM™12'IM§BC,),0B2H£<2:¥LM6/+ ),0 ƒ=9<0182LI.o)3FÀ9½o6/+.I £ˆ+ 9<+:È Ê¤¥¦9<0·¢¨2 o9<¿<2L0À›œ+M6/F 6/012*6ˆ›‚o™B2*2:I©o)3FÀ9ˆM6/+MIY6<›¾£ˆ9<+jÈ ´ÊmQ¹¡9<™´¢_9°È Újý ê/Õfʃ={Åh),Cž£/2L+MFG9<0ŠÈ Újý êfè<Êm={9<018 Åh;1C3C,)ž£<9ˆ0 È Újý ê/êfʆ§1+M6/§¨6/I.2:8«IM;1¥T™¥:6/0 1812:01¥L2O¢_9ˆ0181I7¢_9<I.2:8K6<0 È Ê‹›œ6/+š¥:6/0f£<2:0fo)36/0_9<C]§1+.6/¢1C,2LFGILQ u. ?. ê. z Lm. A{BBBAIê. Ä. sm. m. éÝ = k. óÝ. £. Ý. ý. þ. ‹yz. éÝ =. ƒ.

(26) 0/. . àP). /.14jžæv034. š. ¢ñ2464 ñ.'ž,™1¦. â1¤"›y¤20v £0œ›. Ÿ˜ 6*¢¨2‹§1+M9<¥LM),¥:9<Cs=–)3Ÿ)3IŸI.6/FH2Lo)3FG2LI]IM;BÄH¥:)32:0fM6V¥T™B6h6/I.2‹M™12‹I.FG6{6<M™1),01-7§_9ˆ+o9<FH2LM2:+Ÿ™12:;1+.),I©o),¥:9<C,CžP/= ¢fPª§1C36<MM),01-ŽI.2L£<2:+o9ˆCh¥L;1+.£<2:Ià9ˆ018e¢fPª¥T™16{6/I.),01-7o™_9½% 7™1),¥T™eIM2:2LFGIŸFH6/I.]+.2¦9<C3),I.M),¥ˆQ>¹¡2†¢1+M)32 P5§1+M2LIM2:0f u ‹6G6ˆo™12L+V9ˆ§1§1+M6/9<¥T™12:IšM6G812mo2L+MFH),0125M™12ªIMFH6h6<M™1),0B- §_9<+o9ˆFG2mo2:+.I:Q Ðu0º2¦9<¥T™ºI©o+o9½o;1Fo™12¶I.FG6{6<M™1),01-À§_9<+o9ˆFG2mo2:+.I5¥:6<;1C,8­¢¨2¶¥T™16/I.2:0þ¢fPŠFG9½¼h),FH),¸:)301-G9<0º9<§1§1+.6¦¼B) ± FG9ˆo2A¥L+M6/I.I©±s£<9ˆC,),819ˆo)36/0'IM¥L6/+M2A 7™1)3¥T™« E9<I#812Lo9<),C32:8°¢fP Å{;1C,C3)3£ˆ9<0ºÈ Újý ê/êfÊY›œ6/+79ÀDE6¦¼qFH6{812:C ã 21'È Ê Ú È È ÊMÊ Ú o+M9<¥:2 43 ÐmÈ Ê Ù ÐmÈ Ê ÈÉÞ/Ê . HAL author manuscript. k. ƒ. ‹yz. S. ±. "?. C. Ô. M. éÝ. Q. Vÿ. C. Ý. Ô. éÝ. Ý. 6587. º. éÝ. Ô. inserm-00138554, version 1. 7  ™12L+M2 ),I]o™B2ŽC,6/-½±uC,)3¿<2LC,),™B6h6{85¥:6<0´M+M)3¢1;Bo)36/0O6ˆ›_),018B)3£{),81;19<C _= ¾È Ê :9    È Ê<G),IM™12E)30B›œ6/+.FÀ9½± M),6/0 FG9ˆo+.)ž¼ 9 ¨È Ê    È Ê < ={9<0B8 È Ê ¾È Ê Ù =5 ),IFH),0´;1Iào™B2#¥L6/ 0f; £/ 2L+M-/2L8À™12LIMIM),9<0H6<›¾M™12 §¨2:0_9ˆC,),¸L2:8ºC,6<-ˆ±uC3),¿<2LC,)3™16h6{8  ;  9 È Ê ¾È Ê Ù 65 < 9<018 5 È > È ‚Ê©Ê  > È ¾Ê ]Q!Æ*I¤),0 ª+M9jP È Újý/ý Ù/ʃ=1)3› E2¤),0fM2:+M§B+M2L#o+M9<¥:2 3 ÐmÈ Ê Ù =5 7 ÐLÈ Ê  9<IV9<0«2 ¾2:@¥m? o )3£<2O0´;1F¶@? ¢¨ 2:+76<›§_9<+M9<FG2mo2L+MI#6/+ 9<IŽM™12ªFG6{812LC>812:-<+M2:2LIV6ˆ››œ+.2:2:8B6/F= 21ÀÈ Êš)3Iš2:³´;1)ž£<9ˆC,2:0fšM6G9ˆ0ÆVЩD ¥:+.)3M2:+M)36/0þÈÍÆV¿½9<),¿ˆ2<= Újý Þ Û ÊmQ Æ*0B6<o™12L+H9<§1§1+.6f9<¥T™ ),0fo+.6h81;B¥:2:I w'Ψl ^st l ^µ¿´016j 7C,2L81-/2<=‹¢fP B¼h),01-­o™B2°0{;BF¶¢¾2L+!6<›*8B2:-/+.2:2:IH6<› ›œ+.2:2:8B6/F M6·2:I©o)3FÀ9ˆM2M™12Š™_9<¸:9<+M8̛œ;B01¥LM),6/0»Èœ2<Qç-1Qž=V؋; M9 c ` w<x ,= Újý ê ýhé ÿ*9ˆI.o)32Š9<0B8),¢1I.™1),+M9<01)s= Újý ê ýBé A+o9¦P/= Ú¦ý/ý Ù/ʃQ¤¹¬2¶o™´;1IA;1I.2 o™12 +.2:CÃ9½o),6<0ŠC,)301¿´),01-Ho™12 FH6h8B2:C8B2:-/+.2:2:Iª6<›Y›œ+.2:2:8B6/F9<0B8ºM™12 I.FG6{6<o™B),01- §_9ˆ+o9<FH2LM2:+ M6G2m£ˆ9<C,;_9½o25o™B2¤I.FG6{6<M™1),01- §19<+o9<FH2LM2:+LQÐu01812:2L8>=@)37)3Iš2¦9<I.),2:+šM6HI.§¾2L¥:)ž›aP 9H0{;BF¶¢¾2L+*6<›à812:-/+.2:2LI*6<›à›œ+.2:2L816/F

(27) o6'2LI.M),FG9ˆo2¤9G-<)3£/2L0Š¥:;B+.£/2ˆ=‚+M9ˆo™12L+VM™_9<0KI.§¾2L¥:)ž›aPK9HIMFH6h6ˆo™1)301§_9ˆ+o9<FH2LM2:+:Q ß_6/+!2m¼B9<FH§1C32<=Ž)ž›5 E2« Ž9ˆ0´Ào6¡2LI.M),FG9ˆo29¬I©o+o9ˆ),-/™fGC,),0B2<=‹ ‹2Š¥T™16{6/I.2Š9¬0´;1FO¢¾2L+À6<› 812L-/+M2L2:I#6<›Ÿ›œ+M2:2L816/F$2L³´;_9<C>o6ÀÙh=B 7™B),C,2ª9 ³´;_9<8B+o9ˆM),¥A¥:;B+.£/2¤™_9<I#Õ!812:-<+M2:2LIV6ˆ››œ+.2:2:8B6/FQ ± E. ¹9. WÝ. é Ý ?Ÿ. éÝ. ~Ý. þ Vÿ. "?. é. é Ý ? Ý. W Ý þ éÝ. éÝ. º. W. é. é. "?. ü. “. é. Ô. ?. Ü. Lî. u. \î. ,ؓî. ½. Ô ‹yz. Ý. º. º. <W. . éÝ. Ô. S. Ô. Ê. . . Ô. qü ú eöàü:øHõ A. B. $. #{. . ¹¬2 _+MI©#§1+M2LIM2:0f#o™12A¥L6/FH§1;Bo)301-!9<C3-/6/+M)žo™1F«=´o™12L0qu ‹6HIM),FO;1CÃ9ˆM),6/0ÀI.o;B81),2LI ã 6/0125M6H¥L6/FH§_9<+M2A6<;1+ +.2:IM;BC3oIYo6ªo™B6/IM2#6<›%Ñ#),2LC,IM2L0 c ` w<x VÈ Újý/ý Ù/ʃ=´9<018Ho™12#6<o™B2:+Yo6¤),C,C3;1I.M+o9ˆM2š9eFH6/+.2š+M2¦9ˆC,),I©o)3¥šIM)3M;_9ˆM),6/0>Q 1. ÚÖ.

(28) /. ‘),+. -/.10. ¤7æ¦. 4¨›!ž„ y.'2. ˜š™12†2:I©o),FG9ˆM2:8¤§_9<+o9ˆFG2mo2:+ V E9<IŸ6/¢Bo9<),012L8e¢fPªo™B2‹+.6/¢1;1I©¯K9ˆ+M³´;_9<+.8Bà9ˆC,-/6/+.)3M™1FÈɯK9<+.³{;19<+M8B:= Újý<Ü Õfʆ 7™1)3¥T™)3I79H¥L6/F¶¢1)30_9ˆM),6/0'¢¨2Lu ‹2:2L0­9!ÑV2m šo6/0h±u4V9ˆ§1™1IM6<0K9<C3-/6/+.)3o™BF 9ˆ018K9 I©o2:2L§¾2LI.*812:I.¥:2:0f 9<C3-/6/+.)3o™BFQ]˜š™1)3I‹9ˆC,-/6/+.)3M™1F )3I†FH6/+.2#I©T9<¢BC,2šo™_9ˆ0HM™12*Ñ#2L šM6/0h±Ò4#9<§1™BIM6/0°9ˆC,-/6/+.)3M™1F ¢B;BE§B+M2:I.2:+©£/2:I )žoIV›Í9ˆI.ª¥:6<0´£<2:+.-/2:01¥L2G§B+M6/§¨2:+©uPŠ012:9<+5o™12OFÀ9½¼h)3F¶;1F«QA˜6°¢¨2 IM;1+.2 6<›†™_9¦£{),01-q9'§¨6/IM)žo)ž£/2O›œ;10B¥Lo)36/0 9ˆ¤9ˆC,CI©T9<-<2:Iª6<›Yo™12H9<C3-/6/+.)3o™BF=@ E2H+M2LI.M+M),¥mo2L8¬9ˆC,CM™12 IM§1C3),012 ¥L6h2mÄH¥:),2L0foI o6q¢¨2!§¾6/I.)3M)3£/2e›œ6/+ 9<C3C MQ ˜š™1),IH+M2LI.o+.),¥mo),6<0 8B6h2LIÀ016<H™_9¦£<2Š9ºFÀ9 .6<+G9ˆ8B£/2L+MIM22 ¾2:¥m'6/0²o™129<§1§B+M6¦¼h),FG9ˆo)36/0>= 7™1),C32 ¢¨2:)301-¶£/2L+.Pq¥:6<0´£<2:01)32:0f50´;1FH2:+.),¥:9<C,CžP/Q¹¬2¤9<C,I.6 ),FH§¾6<IM2:8«9 §¨6/IM)žo)3£{)žuPÀ¥L6/01I.M+o9<)30fš›œ6/+Žo™12A£ˆ9<+.)Ã9<01¥L2 §_9ˆ+o9<FH2LM2:+:Q ¹ ™B2:0 ¡),IH£/2L+.PÌI.FÀ9ˆC,Cs=š0´;1FH2:+.),¥:9<CV§B+M6/¢1C32:FHIÀFG9¦PÌ9<+.),I.2<Q ¹ ™12L0 DC Ú Ö E =# ‹2 ;1I.2:8q9<0'9<C3M2:+M019ˆo)ž£/2V›œ6<+MF¶;1C,9e6<›‚o™125C36/-ˆ±ÁC,),¿ˆ2:C3),™16{6h8«ÈÉÙ/ʆ¢19<IM2L8°6/0°9eM™1),+.8h±u6/+.812:+‹2m¼h§_9<0BIM),6<0°),0GM™12 2ƒ¼B§B+M2:I.IM)36/0G6ˆ›¾M™127C,6/-ˆ±ÁC,)3¿<2:C3),™16{6{8>Q‚˜š™´;1IL={ ‹27+M2:§BCÃ9<¥L2:8!o™12šu ‹6ªM2:+.FGIY6<›@o™B27›œ6<+MF Ú C,6<-@È Ú GFHÊ ¢fHP F GF /Ù @FJIq 7)3oK™ F I.o9<0181I°›œ6/.+ F ,L È È ÊMÊh2ƒ¼B§ŸÈ ÊÀ6/+ F L È È ÊMÊB2ƒ¼B§ŸÈ ÊmQ óÝ. HAL author manuscript. é = E. *J. ¹. . . ‹. Ý. inserm-00138554, version 1. ’” . X3 @€’. €. E. ?. =RQ. /. Í. ·. ´. =. . Í. z. M. ‘)—(. «€. º. Q. z E. ]_^. ´. r. z. ¿. =. h. ON. ޞæ›y¢ ¯¢ñžR2. E. Lt. =RQ. u w. E. =RQ. ?. ·. Í. =. ´. z. Í. Q. . ]¾^. ´. r. z. ¿. =. KT. E. . º. Lt. =RQ. u w. E. =RQ. =RQ. PN. '7æ¤M yžæ4j™­¢ . 151¬. ¬¹ 2¶¥:6/0B81;1¥LM2:8þ9ÀI.),F¶;1C,9ˆo)36/0«I.o;B8BPM6'),0f£<2:I.M),-f9½o2OM™12¶Io9ˆFG§1C3),01-H§1+.6/§¾2L+.M),2:I*6<›ào™B2!¯KJ0_Ý]® ›œ6/+ hQ ;1+9ˆ),F  E9<Io6V¥:6/FH§_9<+.2†M™12EI©T9ˆM),I©o),¥:9<C´§1+M6<§¾2L+.o)32:IŸ6<›1M™12E§1+.6/§¨6/IM2L8 FG2mo™16{8e 7)žo™eM™12Ž®†¯ 9<C3-/6/+.)3o™BF ;BIM2:8«¢fPqÑV)32:C3IM2:0 c ` w<x *È Újý/ý Ù/ʃQß_6/+Žo™B2AIM2:C32:¥mo2:8«£ˆ9<C,;12*6<›M™12A£ˆ9<+M),9<01¥:2A§19<+o9<FH2LM2:+ {=  ‹2A-/2:0B2:+o9½o2:8 »),018B2:§¨2:01812L0f7§_9<),+.IAÈ Ê†6<›]IM;1+©£{)3£ˆ9<C¾M),FH2:I† 7)3o™Gu E6!I.M+o9ˆo9O6<›Ÿ2:³´;_9ˆC‚Io9ˆFG§1C32 I.),¸:2*9<018À 7)žo™G6/01C3PH6/0B2*IM;B¢ .2:¥meÈ Ú ÊY)30'2¦9<¥T™ÀI.o+M9ˆo;BF 6<›>2¦9<¥T™°¥LC,;1I©o2:+LQÆ*0'2ƒ¼B9<FG§BC,2*6ˆ›>o™1)3I u ‹6ˆ±uIM9<FH§1C,2¤FG6{812LC] 7)žo™812:§¨2:018B2:01¥L2H¢¨2Lu ‹2:2L0­IM6/FH2O6ˆ›ào™12O),0181)ž£{),81;_9ˆC,IŽ ‹6/;1C,8K¢¾2O9ÀI.M;18BP6<›Y9 81)3IM2:9<IM2¤),0«9!0{;BF¶¢¾2L+¶È eʎ6<››Í9<FH),C,)32:I† 7)3o™ Ù ¥:6/+.+M2LIM§¨6/0181)301-GM6G™´;1I.¢_9<0181I¶È Ú ÚÊ 9<0B8« 7)ž£/2:IOÈ Ù Ú ÊmQ‹ß@6<+š2¦9<¥T™IM),FO;1CÃ9ˆM),6/0À+M;10«6<› +M2L§1C,)3¥¦9ˆM2:I¤ÈsèˆÖ/Ö ;101812L+ 9<018KÙ<Ö/Ö ;10B812:+ .Êm=1M™12ª+o9<0B816/F £ˆ9<+.)Ã9ˆM2:IE ‹2:+.2e-/2L012:+M9ˆo2L8K¢fP'M™12A›œ+o9<)3C3uPGFG6{812:C>9<Iš›œ6/C,C36– 7I ã Ú Ú ÙO)ÉQ×)ÉQ×8‚Qà2m¼h§]È Ú Ê7+M9<01816<F £ˆ9<+M),9ˆo2LI  k. 8 . P . . sm E z A m E. . K. G. ?. ADCFE. CFE. =. €. ?. H. G. ?. ?. €. =. A þ J8?. <AŒCFE z?. r. ê. z. E. ?. þ. <A{BBBADN A G. ?. <A. Ú/Ú.

(29) m E. =. ?. )sQç)sQç8>Qà-f9<FHFG9qÈ Ú ¦Ú <Ê. Ú. ‡ E„A JM?. ’” A. <A$BBBAINA. . E. =. ’” . ’”‡ E—B. š˜ ™12¤IM;1+©£{)3£ˆ9<C%o)3FG2LI7 ‹2:+.2O016ˆVC32L›a©±Áo+.;101¥:9ˆo2L8·Èœ2:0fo+©P«M),FH2:Iš2L³{;19<CŸM6G¸L2:+.6´ÊmQŽÆVC,C>›Í9<)3C,;1+.25o)3FG2LI  ‹2:+.2«¥L2:01I.6/+M2L8Ì9ˆ B¼h2:8˝M),FH2:IqÈ Ù/Êe8B2Lo2L+MFH),012L8 9<I o™12'£ˆ9<C3;12'o™_9½¶ E6<;1C,8²¥:2L01IM6<+ Ú Ö&% Ȝ),0 2ƒ¼B§¨2:¥mT9ˆM),6/0_ÊE6<›M™12ª2:0fo)3+M2ªIo9ˆFG§1C32<Q ¹¬2 ;1IM2L8¬¥L;1¢1),¥!I.§1C,)3012:I*M6«9<§1§1+.6j¼h)3FÀ9ˆM2¶2¦9ˆ¥T™¬™_9ˆ¸¦9<+.8º›œ;B01¥LM),6/0>Qe˜š™12!0´;1F¶¢¨2:+A6<›‹¿´016<oIA E9<I ꛜ6/+«9<C,CAI.),F¶;BCÃ9ˆM),6/01ILQ ß@6<+qM™12 _+MI©K+.2:§1C3),¥¦9½o2º6<›¶2:9<¥T™ I.),F¶;BCÃ9ˆM),6/0ÇȜ)sQç2<Qž=5›œ6/+«9 -/)ž£/2L0 ²9<018 0´;1F¶¢¨2:+#6<›-/+M6/;B§1I ¤ÊŽ E2¤2L£ˆ9<C3;_9ˆo2L8K)302:9<¥T™ŠI.M+o9ˆM;1F9 £<9ˆC,;12¤6<› QL ;1IM)301-GM™12 B¼h2:8Š812L-/+M2L2:I 6<››œ+M2:2L816/FFH2Lo™B6h8>Q*Åh)301¥:2¤o™12e™_9<¸¦9ˆ+M8K›œ;10B¥Lo)36/0K)3I59H¥:6/01I©T9<0f5›œ;B01¥LM),6/02:³´;_9<CŸo6 Ú =¨ ‹2¶™_9<8o6 I.§¾2L¥:)3›aP­9«+.2¦9<I.6/0_9<¢1C32 £<9ˆC,;12 ›œ6/+5M™12GI.FG6{6<M™1),01-°§19<+o9<FH2LM2:+ª),0º6/+.812:+AM66/¢hT9<)30¬9qC,)3012¦9ˆ+5™_9<¸:9<+M8 ›œ;10B¥Lo)36/0¥:C36/IM2'M6þ9ºC3),012:9<+e›œ;B01¥LM),6/06<›#o)3FG2ˆQ¬˜š™B2«0´;1FH2:+.),¥:9<CŽ2L£ˆ9<C3;_9ˆM),6/01I¶9<C,C36– ‹2:8;BI¶o6 _018 9ŠI.FG6{6<o™B),01-Š§19<+o9<FH2LM2:+ ¥L6/+M+.2:IM§¨6/018B),01-ŠM6¬9ŠFH6{812:CŽ8B2:-/+.2:2:I!6<›7›œ+.2:2:8B6/F ¥:C36/IM2'M6þÙ²ÈÍ¢¨2Lu ‹2:2:0 ÙhQ×֊9<0B8²ÙhQ Ú ÊmQŠ˜š™B2:+M2:9ˆ›ao2L+ QL  Ž9ˆIOo™12ÀIo9<FH2À›œ6/+ªo™12°¯ +M2:§BC,),¥:9ˆo2LIO6<›šM™12'I.),F¶;1C,9ˆo)36/0>Q«˜š™12 2LFG§1)3+M)3¥¦9<CI.T9ˆ018_9<+.8¬812m£{)Ã9ˆM),6/S0 R UT È /Ê* E9<Ie2LI.M),FG9ˆo2L8>=]9<018ºu E62:I©o),FG9ˆM6/+MIA6<›‹I.o9<018_9ˆ+M8¡2L+M+.6/+  ‹2:+.2¶¥:6/FH§1;BM2:8 é R + ÀÈ <Ê WV 9<018KM™12¶Io9ˆ018B 7),¥T™­2LI.M),FG9ˆo6/+ R + 'È /Ê V X ¦QV˜š™12 ™fP{§¾6ˆo™12LIM),I Ö ¥¦9ˆ0þ¢¨2OM2:I.M2:8þ;1IM)301-q9'IM¥L6/+M2¶M2:I©GÈsDE6/FHFG2L01-/2LIA9<018ºÆ*0B812:+.IM2:0‚= Ú¦ý/ý è/Ê7¢1;B  ‹2ª816G0B6<7§1+M2LIM2L0´V+M2LIM;1CžoI7;1I.),01-!o™1)3IŽo2LI.#™12:+.2<Q Y[Z ]w \:x,c  w<l t | \ _ z ^_cmlo,c ` ß_6/+ o™129<0_9ˆC3P{IM2LIG6<›Vo™12«;101¥L2:01I.6/+M2L8ÌC,)ž›œ2'o)3FG2LI:=Yo™12«+M2LIM;1CžoIG9<+M2«IM;1FHFG9<+M)3¸:2:8²)30˘9<¢1C32 Ú Q ¹¬2¶6/¢1I.2:+©£/2:8þ9À0B2:-f9ˆM)3£<2¶¢1)Ã9ˆIV›œ6/+ H›œ6/+VIMFG9<C,CŸ0´;1F¶¢¨2:+*6ˆ›Y-/+M6/;B§1I:Q¤DE6/0f£<2:+MI.2:CžP/=> ‹2 6/¢BT9ˆ),012L8­9<0 6j£/2L+©±Á2:I.M),FG9ˆo)36/0H6<› ¤ 7™B2:0'o™B250´;1F¶¢¨2:+E6ˆ›%-/+M6<;1§1IŽ)301¥:+.2¦9<I.2:8>QYÑ#2L£/2L+.M™12:C32:IMIL=1o™1)3I‹¢B)Ã9<I‹812:¥L+M2¦9ˆIM2:8  7)žo™!),01¥L+M2:9<IM)301- ›œ6/+†9A-/)3£<2:0!£<9ˆC,;1276<› hQàÆVIY2m¼h§¾2L¥LM2:8>={o™127Io9ˆ018B 7),¥T™GI.o9<018_9<+.8G2L+M+.6/+Y2:I.M),FG9ˆo6<+ 6<› V X @  E9<I IMFG9<C3C,2:+ªo™19<0¡o™B2°¢_9¦P/2:I.)Ã9<0I©T9<0B8_9<+M8²2L+M+M6<+O2:I©o)3FÀ9ˆM6/+ aV eQ ØE6ˆo™q2:I©o),FG9ˆM6/+MIš;10B812:+Ò±u2:I©o)3FÀ9ˆM25o™12ª2LFG§1)3+M)3¥¦9<C¾I.T9ˆ018_9<+.82L+M+M6<+¤ È R È fÊ.ÊmQ Y[Z ]w \:x,c5~«w<l t | \ _ z ^_cmlo,c ` ˜š™12GIo9<FH2G-<2:012L+o9<Co2L01812L01¥:)32:Ie ‹2:+.2À6/¢BIM2:+©£/2L8· 7™12:0¡M),FH2:IA ‹2:+M2G¥:2L01IM6/+.2:8²9ˆ Ù¡È͘9<¢1C32 V. sm ?. HAL author manuscript. Â. ò . 1. ˆ. Ô. Š. . . ². inserm-00138554, version 1. Ô. ˆ. Š. . ². B ûB. ü. uu . ?. ‹yz Ý Š—Š. Ý P?. uu. Ý. "ü. ‹yz. Ý P?. þ. þ. ‹yz. W. Š—Š. þ. Ý. Ý. }. ‹yz. 3 ÿ Ý. þ. ã . ‹yz. W. Š—Š. ‹yz Ý Š—Š. Êÿ. B ü. þ. B. Ý. þ. m~?. ÚÙ.

(30) ÀÙ £{Ie˜9<¢1C32 Ú ÊmQHÑV2m£/2L+.o™B2:C,2LIMIL=o™12HFH2¦9<0­£ˆ9<C,;B2H6ˆ› ' E9<Ie-<+M2¦9½o2:+AM™_9<0 q)30þM™12!¥:2L01IM6/+.2:8·¥:9<IM2ˆ=  7™_9½o2L£<2:+M™12EIM9<FH§1C,2†IM)3¸:2<QÆ*I2m¼h§¾2L¥LM2:8>=/M™12EI©T9<01819<+M8¶8B2L£{)Ã9ˆM),6/0¤6<› š Ž9ˆIàCÃ9<+.-/2:+])30eo™B2E¥:2L01IM6<+M2:8 M™_9<0q),0°o™B2¤;B01¥:2L01IM6/+.2:8Š¥:9<IM2ˆQ È ´Ê fe =š 7™1),¥T™ï)3IGo™B2:6/+.2Lo)3¥¦9<C3C3P²C32:IMIÀ¢1)Ã9<I.2:8>=š E9<I ˜š™12Š2LI.M),FG9ˆo6/c+ b È ´Ê d 9<C3FG6<I.š)3812:0fo)3¥¦9<C¨o6 hQ Y Œ ^ v<|{loc  w<l t | \ g z ^_cmlo,c ` ß)3-/;1+M2 Ú ),C,C3;1I.M+o9ˆM2:I#o™12¶M™12:6/+.2LM),¥¦9ˆC9<018º2:I©o)3FÀ9ˆM2:8­¢_9ˆIM2:C3),012O™_9<¸¦9ˆ+M8­›œ;101¥mo),6<01I5›œ6/+A9°IM)301-/C32 I.),F¶;1C,9ˆo)36/0 6ˆ› Û Ö/Ö·IM;1¢ .2:¥LMIK9ˆ018 9¡£<9ˆ+M)Ã9ˆ01¥:2Š§19<+o9<FH2LM2:+ Ö çÛ Q ¹¬2º9<C,I.6+M2L§1+M2LIM2:0fM2:8M™12 2LI.o)3FÀ9½o2:8HFG9<+M-/)30_9<C1™19<¸¦9<+.8G›œ;10B¥Lo)36/0G 7™B),¥T™G E9<I‹2:I.M),FG9ˆo2L8G;BIM),0B-¶9e§B+M6/§¨6/+.M),6/019<C1™_9<¸:9<+M8GFG6{812LC  7)žo™16/;h›œ+M9<),CžuPA£<9ˆ+M)Ã9ˆ¢1C,2LI:QŸ˜š™12ŽFG9<+M-/)30_9<Cf™_9ˆ¸¦9<+.8O›œ;101¥mo),6<0¶),IŸ¥:6/0B012:¥mo2:8  7)žo™OM™12Ž9¦£/2L+o9<-<2Ž™_9<¸:9<+M8 )30Ào™12A§¨6/§1;BCÃ9ˆM),6/0>={9<0B8«¥L6/+M+.2:I.§¾6/0B81IŽo6¶M™12A™_9<¸:9<+M8'›œ6/+Ž9<0q9¦£/2:+M9<-/2A£ˆ9<C,;B2*6<›]o™B25›œ+o9<)3C3uP £ˆ9<+M),9<¢1C32 9<FH6/01-¤o™12AI.;1+.£{)ž£h)301-¶)30181)3£{)381;_9<C3I:Q˜š™´;1I7)30Ào™1)3IŽ2m¼B9<FH§1C32<=hM™125§¨6/§1;1C,9ˆo)36/0À™19<¸¦9<+.8'›œ;101¥mo),6<0°9<018 M™12Š),0B81)3£{),8B;_9<Cš™_9<¸:9<+M8̛œ;B01¥LM),6/0»Èœ;1IM)301-¡M™12K›œ+o9ˆ),C3uP²FH6{812:CÃÊ!812m£{)Ã9ˆM2KFH6/+M2K9<018ïFH6/+M29<IÀM),FH2 §_9ˆIMIM2LI:=š¢¨2:¥:9<;1IM2«o™12FG6<I.!›œ+o9<)3CšIM;1¢ .2:¥LMI'™_9¦£/2K9<C,+.2¦9<8hP81),2L8>Q™12«¥:6/0 _812:0B¥:2Š¢_9ˆ0181IG›œ6<+!M™12 2LI.o)3FÀ9½o2:8q¢_9ˆIM2:C3),012ª™_9ˆ¸¦9<+.8›œ;101¥mo)36/0° E2L+M2O6<¢BT9<)3012:8«;1I.),01-!o™12¤I.o9<018_9ˆ+M8«2:+M+.6/+#2:I.M),FG9ˆo6<+Ž6<›M™12 I.§1C,)3012A§_9<+M9<FG2mo2L+MI V X ¶Èœ;1IM)301- V  7P{),2LC,812L8«0B2¦9<+.C3PÀM™12ªIo9<FH2ª+M2LIM;1CžƒÊmQ ð Ý.  . Ý. ¯?. Ý. ‹yz. Ý. º. ù. ”ó Ý :ÿ. ”ó Ý. ó ². Š. ². Ý. þ. HAL author manuscript. . Þ . ?. B. inserm-00138554, version 1. . ‹yz. þ. /. hiN. ‘)„à. '20¥›!žæv¤7. ‹yz. W. c. ‹yz. Š—Š. þ. Š—Š. þ. N. žR7R7 1¢ ñ›y¤M ñžR4. ™. ¡¹ 2Ž9<C,I.65¥¦9<+.+M)32:8¶6/;hY9*81) ‚2L+M2:0fI.),F¶;BCÃ9ˆM),6/0¤I.M;18BPOM65),C3C,;1I©o+M9ˆo2Yo™12E³{;19<C,)žuPe6ˆ›¨M™12Ž2LI.o)3FÀ9½o),6<0 ›œ6/+V9À016<0h±uC3),012:9<+V™19<¸¦9<+.8K›œ;101¥mo)36/0>Q*Æ Io9<FH§1C32e 7)3M™ŠIM)3FG)3CÃ9<+Ž›œ2:9ˆo;B+M2:I59<IVM™12 J9ˆ³{;B),8Š¥L6/™16/+©HÈÍI.2:2 I.2:¥LM),6/0ïè/Ê! E9<I'-/2L012:+M9ˆo2L8 㠝o™12L+M2K E9<IqÙ{= Ü/ý ê¬IM;B¢ .2:¥moIq9<018Ì£ˆ9<+©P{),01-¬-/+M6/;B§ÌIM)3¸:2:IL=7¢¾2mu E2L2:0 Ú Õ 9<0B8ïÙ<ÕfÙ­IM;B¢ .2:¥moI'¢fP -/+M6<;1§>=ªÈœ¢1;BÀ 7)žo™16<;BH2m¼h§1CÃ9ˆ0_9ˆo6<+.P£ˆ9<+M),9<¢1C32:ITʃQ̘š™12«›Í9<),C3;1+M2'M),FH2:I  E2L+M2 -/2L012:+M9ˆo2L8²;1IM)301-º9ŠFG) ¼{o;1+.2'6<›š¹¬2:),¢B;1C,C‹81),I©o+M)3¢1;BM),6/01I'Ȝ›œ6/+eI.M+o9ˆM;1F Ú ã Ö Õ/&è jµÈ é Ù<Ö Ö Ö Ú ÕfÊ Ö ×Ü &è jµÈ é Ù<Ö Ö Ö Ú ÖfÙ/Ê é ›œ6/+EI.o+M9ˆo;BF

(31) Ù ã Ö Õf&è jµÈ é:Ú è Ö Ö Ú Ö/Þ/Ê Ö åÜ &è jµÈ é¦Ú è Ö Ö Ú ÖfÞ/ÊYʃQÆ IM™_9<+.2:8 ›œ+M9<),CžuP°£<9ˆ+M)Ã9ˆ¢1C,2ª›œ6/+*2:9<¥T™º-/+M6<;1§Š6<›†IM;B¢ .2:¥moI5 E9<IA-/2:0B2:+o9½o2:8º;1I.),01-'9'-f9<FHFÀ9!81),I©o+.),¢1;BM),6/0·Èœ 7)žo™ Ö Ù/ʃQ˜š™B2†819ˆT9Ž ‹2:+M2YC32L›a.±so+.;101¥¦9½o2:8¤9<0B8e+.),-/™f.±Á¥:2L01IM6/+.2:8¤9ˆŸ9 B¼h2:8ª£ˆ9<C,;B2<=½9<018ªo™12§¨2:+.¥:2L0´o9<-/2 ÚÕ . . . Lm. B. sm. B. A. B. B. Lm. A. B. º. B. . ~?. B. *. Lm. A. B. A. B. º.

Références

Documents relatifs

After a general introduction to these partition-based strategies, we study two cases: a classical one in which the conditional density depends in a piecewise polynomial manner of

In [14], a Maximum Likelihood (ML) technique has been proposed for estimating the amplitude parameters from the three-phase signal, but it is not suited for systems with phase

This paper considers the problem of estimation in the stratified proportional intensity regression model for survival data, when the stratum information is missing for some

Thanks to a simulations study we see that the performance of the estimator is satisfactory with Gaussian and Binomial distributions, even if, by comparison, kernel and splines

After having shown the benefit of Fisher pdfs to model the texture of high-resolution PolSAR data, we propose to imple- ment this distribution in the ML texture tracking algorithm..

After having reminded the general ML texture tracking method, the benefit of the modeling the texture τ with a Fisher Probability Density Function (PDF) is exposed and

Abstract: We wish to estimate conditional density using Gaussian Mixture Regression model with logistic weights and means depending on the covariate.. We aim at selecting the number

Penalized least squares regression is often used for signal denoising and inverse problems, and is commonly interpreted in a Bayesian framework as a Maximum A Posteriori