• Aucun résultat trouvé

Work increases the incidence of carpal tunnel syndrome in the general population.

N/A
N/A
Protected

Academic year: 2021

Partager "Work increases the incidence of carpal tunnel syndrome in the general population."

Copied!
18
0
0

Texte intégral

(1)Work increases the incidence of carpal tunnel syndrome in the general population. Yves Roquelaure, Catherine Ha, Marie-Christine Pelier-Cady, Guillaume Nicolas, Alexis Descatha, Annette Leclerc, Guy Raimbeau, Marcel Goldberg, Ellen Imbernon. To cite this version: Yves Roquelaure, Catherine Ha, Marie-Christine Pelier-Cady, Guillaume Nicolas, Alexis Descatha, et al.. Work increases the incidence of carpal tunnel syndrome in the general population.. Muscle and Nerve, Wiley, 2008, 37 (4), pp.477-82. �10.1002/mus.20952�. �inserm-00256944�. HAL Id: inserm-00256944 https://www.hal.inserm.fr/inserm-00256944 Submitted on 18 Feb 2008. 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.  

(3)   

(4)  

(5)  "!#$&%('*)  +%-,.( +/0 123 4 4+ %56$)7%8 28. Muscle & Nerve 2008;:epub ahead of print. HAL author manuscript. 9 :; <=>?A@(;BDCE@F2;4GIHKJMLNGPO*CEQSRT;+FVUDW;MXYCGIHZJ\[GIH]C+F2UD;4^VO_R`FaUN<SQSUbW; c";BbU8;+F^VO*CdTe&GIHKJMLNGPf@(UbBDB8C+@hgi; j UDk4>lBDC <2G HZJ1LNG-mnB8;+oUp<qJr;A<kCEQSRCG HZJ\sG-m#WWT;EQNQt;Yuv;kBD;F2kG cwRJ\sGwfx@e1=nCUDg\y(;ACz@(G HKJMLNG H]C+Fk;AB fn>&BDd y;FV{GTHZJ\sGT|vBDB;W\}2g\y;FVW>WG HKJ~[. inserm-00256944, version 1. \L uvC4y&>&FC Qp>&UF;€dh‚|vFV{>W>grU;ƒ;EQ0dh|P„UDd g U‚>lBD>{lU8;€;+W†C‡WQt ˆCz@Š‰wF2CE:CU8BDG\}Œ‹h= Ž G‘rWU:(;+F<2U’Q2 dhmnW {;+F“<2GOvXn”mnW {;F<2G ‹•^Œ–——ŽŽ\mnW {(;+F<2G ‹F2CWk; [˜Jr „C+FpQt;gr;WQ™†C+WQt š‰wF2CE:&CUbB‚G›}2Wl<SQVUœQN@Qd;ˆ:&;‡UDB8B;”<2CWUœQtCUF2;ŸžŒ}tW  †¡2G\‹•^V— ––w¢†lCUbWQt^pH]Cz@FaU‚kA;4G ‹F2CWTk; sw}Nj0†A|6=_H£GTY¤l¥`¦Gh†C+UDWAQt^pH£CE@F2UDk;G ‹•^V— ––w§G ‹F2CWk; 0¨ E.r©Y++ªCQQSFtU‚y`@QtCEyB8;F2U<V«¬k4C+FV„CB QN@WW;B<VeWd F2>gi;T¬T;+„U8d;‡grUD>BD>&{U8kC‡Bh<S@FV:;UB8BCWTkA;¬A­Y>&Ft«h¬ ­Y>&FV«T^ŒF2;+B‚CEQt;d O*>&FtF2;A<V„T>&WTd;+Wk;_Qp>-®+c•FV>¯2°A9:;<-=x>l?A@(;B8CE@F2;A¬T;^VgiCUbB®±9: =x>?A@(;‡B8CE@F;²ˆkR@(^VC+W {(;+F< °œ¯NF ‹•UDWC‡WTkUCBJrUN<2kBD> <S@F2;\† QtC Qt;gr;WAQ ® ‰wRU<wF2;<2;C+Fk‡Ri<ŒQN@(dAe\­YCA<P<S@„„>&FŒQt;4d‘ye#QSRT;_‹F2;WkRjiCEQtUD>WCB }VW<ŒQtUœQN@Qt;_¯S>F-c@yBbU8k_XY;CBœQtR1† @FŒ:;UBDB8CWk;žŒ}VW<ŒQtUœQN@Q•d;* \;UDBDB;\†CWUœQtCUDF2;+¡-­rU’QSR> @Q•C+W eYk>&Ft„> F2C Qt; <V„>Wl<>&F ° ³q2\ ~

(6) + l.7/´r´µµ-E¶(8 2 +ªqm‘‹h|·GPCEQ8QSFVUy@QtCEyBD;˜¯NF2CkzQVUD>WZ>l¯F2UN<V«]Cgr>W {¸QSRT;˜;+o„>h<2;d „;+F<>&W<z¬›¹qH™}2G y>d eºgiCT<“<]UbWd;+o¬0OP}V»¼ ½h¾¿—l¢À k4>&W¯SU8d;‡WTk;ÁUDWAQt;FŒ:CBN¬O_‰*†G´k4C+FV„CB QN@WW;B <VeWTd F2>lgr; ¬˜|6J\Â~G™;BD;kEQSFt>d UC{lWT>7<SQSUDk ¬Ã}Nj´† |6|*G˜‹F2;+WTkRÄjiCEQtUD>&WTCB™}VWh<ŒQtUœQN@ Qt;º>¯”† QtC QSU8<ŒQtUDk <”CWd |·k>&WT>&grU8k\† QN@(d UD;A<z¬=*=GF2;BDCEQtU:;F2UN<V«.

(7)  ,(' . HAL author manuscript inserm-00256944, version 1. #! 'ªmnW€;+„U8d;g›U‚>lBD>{lU8kCBW;EQN­Y>&Ft«£­YCA<1<2;zQ#@„€UDW]C˜‹F2;WkR]F2;+{UD>&W™QS>ƒ;A<ŒQSUDgiCEQt;´QSR; UDWkUd;WTkA;0>¯O*‰_†ZUbW˜QSRT; {;W;F2CB„>„ @hB‚CEQVU‚>&WZCkk4>&F2dUDW {ÃQS>™;+g\„BD>&eTgi;‡WQ\<SQtC QN@< °wO*CA<2;A<~>¯O*‰*† >kkE@FVFVUDW`{ÁUDW”„(CEQSUD;WAQ2< C+{h;4d § Qp> ¢`—”BDU‚:(UDW{ÁUDW QtR;ˆH]CUDW;  uv>lUF2;]F2;+{UD>lWš­Y;+F2;ŸUDWk‡B@(d;d „F2>h<V„;kQSU:;Bbe]¯SF2>lg §§ KQt>£§§ –(°"H£;dUDkCBCWd™>kkE@„CzQSUD>&W™RUN<SQt>&FŒeZ­rC<\{CEQSR;+F;d ye]giCUDB8;Ad ?A@(;A<SQSUD>&WWCUF; °_}2WTk‡U8d;Wk4;£F2CzQt;A<0>¯1O*‰_† C+WTdšF2;B8CEQSU:;KF2UN<V«<0žp=q=¡0>¯1O*‰*† ­Y;+F2;™k4>lg\„ @Qt;dŸUW F2;BDCEQtUD>W´Qt>K;g\„lB‚>&egi;WAQn<ŒQtCzQN@<z°•‰IRT;1CEQQ FVUy @QtCEyB8;1¯ŒF“CkEQSU‚>&Wh<n>¯*F2Up<t«Z>l¯qO_‰*†˜Qt> ­~> FV«ZC+gr>W {ÃQSR; ;EoT„>7<;d£„;F<2>Wl<ižVm‹h|P¡\­Y;+F2;ÃkCBDkE@(B8CEQt;dh°6m Qp>AQtC+B>¯´GV¤l¥Z„C QSU‚;‡WQ2<iža¥—K­r>gr;WGqŽ –—ˆgr;W ¡ ­Y;+F2;€UDWkB@(d;d”dA@F2UbW{ QSRT;£QSR F;;^ŒeT;C+F˜„;+F2UD>dh°n‰IR;€gr;4C‡W”UDWkU8d;Wk;ˆF2CEQt;]>¯0O_‰*†”„;+F€GD§§§ „;+F<>&WT^Œe;4C+F<w­rC<PRU{R;+F6UbWi;gr„lB‚>&e;drk>g\„C+F2;d#Qt>#@W;gr„BD>&e;4d›„;+F<>&W<vž+°’¦~:(<z°`§h°¥\UDW\­r>lgY;AW C+WTd˜§h°’¤ :h< °§h°œŽ0UbWg ;W`¡z°‰IRT; ;Eo&k; <<qF2Up<t«Ã>¯*O*‰_†´­YCA<n<ŒQtCEQSU<SQVU‚kCBBbeZ<2UD{lWUD¯VU8kCWAQ*¯S>FgYC‡B8;ižp=*=  –° ¡*C+WTd ¯t;g CB8;\žp=* = KŽh°’§ ¡yB@7;^Vk>BDB8C+F­Y>&FV«;F<*CWd1¯t;‡giCB8;\BD>T­›;+FP{F2Cd;­rRUœQt;^Vk4>lBDBCF­r>FV«;+F“< žp=* = ˜°¢¡z°T‰IRT;Ym‹(|™Qt>›­r> FV«1UDWr{;W;+F2CBl­YCA<P–¦ À žV—l¢À OP}2GhŽ—^a¢–¡PUDW\­Y>lgr;Wh°m‹h|<6F2;4CAkRT;Ad RUD{lRT;+Fw:CB@(;A<6UbWi¯V;giCB8;xyBœ@7;^Vk4>&BDB8C+F-­Y>&FV«;F<6žV¤¦ À

(8) 8¤l¢`^V¤l¥ Œ¡6C+WTd›BD> ­Y;+Fw{F2Cd;#<;+FŒ:U8k;A<G7<C‡B8; <6CWd kBD;+F2U8kCB-­rRUœQt;^tk>&BDB8C+F*­r>FV«;+F<qžt¤-z À

(9) S¢`¦^V¤ – p¡ °h‰wR;\m‘‹(| UDW˜giCB8;›yB@(;^Vk>lBDB8C+FP­Y>&FV«;F<P­rC<q¦¤&À

(10) N¦ ^a¥`§ 2°}VW1k4>&WTk‡B’@<2UD>lWGlQSRT;›<ŒQN@(d e0<2R> ­ <·C#RUD{lRT;+F*UbWTkUd;WTkA;~>&¯6O*‰*†´UDW›QSRT;‘­r>FV«UDW {1„>„ @(BDCEQtUD>lW k>g\„C+F2;4d~Qp>#QSR;W>W^N­r>FV«UDW {r„>„ @BDCEQtUD>&W(°.

(11) O*C+FV„CB´QN@WWT;‡BZ<VeWd F2>lgY; žVO*‰_†¡€U8<ŸCŠk>lgrgr>lW kBDUDWlU8kCBÄF2> yBD;g QSRCEQ]¯NF2;?A@(;WQSB‚e F“;?A@(UF2; < <Œ@Ft{;+FVeh° [\c•>„ @B8CEQSUD>W€<ŒQN@(dUD; <rRC4:&;˜F2;+„>FpQt;d™CWWA@(CBUDWkU8dl;Wk4; FCEQt;A<\y;zQN­r;;W]§h°‚¢ C+WTd ¢°N0„;+F GD§§§˜¯S>&FxO_‰*†Ãd;+¯SUDW;Ad´yeZ;B8;kEQSFt>„R eh<2UD>lB‚>&{U8kCB6k+F2UœQt;+F2U8C+s ¾ CWd´y(;EQN­Y;;+W§h° –ÃCWd€°¢1„;+FiGb§§§ ¯S>Fˆ<Œ@Ft{lUDkCB1F2;BD;CA<; >l¯´QSRT; gi;d&U8CW WT;+FV:; °DL ¾ L ¼ m#B’QVRT>T@{R WT>TQ¸kCE@<2;4d >&WBe yeŠ­Y>&FV«G1O*‰*† F2;+„F;A<2;+WQ2<0C™g C 2>F1„F2>„> FNQSUD>WŸ>l¯iCBbBnF2;+{UN<ŒQt;+F;dŸ>&FMk>&g~„;‡W<2CEQtCzyB;¸­Y>FV«^ŒF2;BDCEQt;4dšd UN<;C <2;A<0UW giCW eÃk> @WAQSFtUD; <z° ¾ » †lUDWk; giCW e>l¯wQSR;›UDWdU‚:(U8dA@(CB-F2UŒ<t«˜¯VC4kEQt> F<q>¯*O*‰_†C+F2;›B8; <<qgr>d&U8¯VU8C+yB;\QSRCW ­Y>&FV«„B‚Ck;ˆ¯tCkEQt>F<2GUDW¯S>&F2giCEQSUD>W C+y> @Q›QSRT;ˆUDWkU8d;Wk;]>l¯1O*‰*†”UbW€QSRT; ­Y>&Ft«UbW`{ „>„ @hB‚CEQVU‚>&W UŒ< ;A<“<2;WAQtUDCBlQt>#QtC+FV{;Qw„`F2;E:;WQSUD>&Wi;¯S¯S>&FŒQ2< °ji;E:;+FSQSR;B8;A<z<2Ghd;<V„UœQt;#UœQ2<w:CB@(;#¯NF2>g C„ @yBU8kR;CBœQSR›:U8;+­ „>UbWQtG_BDUœQNQSBD;ÃUDW¯S>&F2giCEQtUD>&W]UN<iC+:CUB8C+yB8;¸>WKQSR;˜FVU8<V«Ÿ>¯\O*‰*†€CQQSFVUy`@QtCEyB8;Qp>£­~>FV«™¯SCkEQt>F<rUDWKQSR; {;+WT;+F2CB™„>&„ @(BDCEQtUD>Wh° ¾ LVL ¾ L ‰wR; ‹F2;WkR }aW<ŒQtUœQN@Qt; ¯S>&FŸc@yBU8k XY;CBœQtR † @FŒ:&;‡U8BB8CWk; QSR;+F;‡¯S>F2; Ugr„B8;‡gi;WAQt;4d C+Wi;+„U8d;‡giUD>lBD>{Uk4C‡B•<Œ@FV:;UBDB8CWk;\<Veh<ŒQ;g ¯S>FPO*‰*† UDWYQSRT;‘{;WT;+F2CBh„>„ @hBDCzQSUD>&Wi>l¯QSR; H]CUDW;C+WTd~uv>UF2;žpH \u6¡wF2;+{UD>WrUbW ; <ŒQt^VO*;+WQSF2C+B‹F2C+WTkA;UDW\§§ ° ‰wR;1CUg >&¯PQSR; „F2;<2;WAQn<ŒQN@(dAe0­iCA<qQt>KCA<“<2;A<“<QSR;1UWTk‡U8d;Wk;1>¯O*‰*†KCk4k>&Fd UbW`{˜Qt>K;+g\„BD>&egi;WAQ <ŒQtCQN@<6C+WTd#QSR;„Ft>&„T>&FNQSUD>Wr>&¯•kC<2; <6CEQ8QSFVUy @QtCEyB8;_QS>\­~>&Ft«\UDW#QSR;{;+WT;+F2CB„>&„ @(BDCEQtUD>Wr>&¯hQSRT;F2;+{UD>Wh° . HAL author manuscript. . . . inserm-00256944, version 1. . . . + 2 5v+ 2

(12) 4 %. w‰ R;0„>&„ @BDCzQVUD>W™UDWkB‚@(d;4d£UDW¸QSRUN<1<SQN@(dAe]k>lg~„FaUN<;dKF2;A<2U8d;WAQ2<Y>&¯QSRT; H \uŠF2;+{UD>lW y;zQN­r;;W#QSRT;C+{;A<6>¯§^a¢`—

(13) — –G¦¤#­~>gr;Wrža¢`§h°NzÀ˜¡6C+WTd —ŽG¥`§ \gi;WržŒ–—h°’— À0¡ ° † @y 2;kEQ2<1­rRT> RCd @(Wd;+Ft{>&WT;€;B;4kEQSFV>d U8C+{W>h<ŒQSUDk]žp|6J\Ân¡¸<SQN@(d&U‚;A<Ã>¯ QSR; @„„;+FBDUg\y<ye˜QSRT; ¯VU:(;´<;‡WQVUDWT;‡B6„R eh<2U8kUCWh<n>¯PQSR;1>&WBeZ¯S> @Fn;‡B‚;kEQSF2>d UDC+{W>h<ŒQSUDk1k4;‡WQt;+F<n>¯PQSR; H ru™F2;{lUD>WY­Y;+F2;n;BUD{U‚y(B8;#¯S>FIQSRT;Y<SQN@(dTeiUD¯-QSR;+e›­Y;F2;F2;A<2UDd;WAQ2<v>¯ QSRT;\d;¯ŒUDW;d {;>{F2C+„RU8knC+F2;C`° WBbe kC<2; <”>¯ O*‰*† ­rUœQSRT>T@QŸ„FtUD>&F RUN<ŒQt>FŒe >l¯ O*‰_† >¯€QSR; <“Cgi; ­~F2UN<ŒQ€­Y;+F2;ÄUDWkB@(d;Ad „F2>h<V„;kQSU:;BbeÃy&;EQN­r;4;‡W§§ KCWTd §§ –°}VWTk‡U8d;WAQxkC<2;A<n>¯O*‰*† ­Y;+F2;1d;¯SUDW;d yeÃy> QSRÃkBDUDWlU8kCB C+WTdˆ;B8;kEQSF2>„R e<2UD>lBD>{Uk4C‡Bxk+F2UœQt;+F2UDC´@<2UDW{£QSRT;K<2Cgi; <SQtC+WdCF2d&U ;4d£„F2>AQp>lk>BDG·­~RU8k‡R]¯S>lBDBD> ­r;4d QSR;.

(14)  

(15) . . 

(16) "!$#!&%'

(17) . (. ). &*.

(18) „ @yBUN<2RT;d F2;k>lgrgi;WdCEQtUD>Wh<z° ¼ ‰w> y&; UDWTk‡B@(d;dG <Vegr„ Qt>&gi< RTCd Qt> y&; k‡B‚CA<z<2UD¯VU8;d C < kBDC <<2U8k „F2>Ty&C+yB; O*‰_† Ckk4>&F2d UDW`{ Qt> QSRT; k>&W<2;Wl<S@-< k+F2UœQt;+F2U8C ¯S>F O*‰_† kBDC <<2U¯tUk4CEQVU‚>&W UW ;+„UDd;g UD>BD>&{U8kCB_<SQN@(d&U‚;T<GNL[nC+WdÃCEQqBD;4CT<SQPQN­~>Ã>&¯PQSRT; ¯S>lBDBD>T­YUbW{˜|6J\ k+F2UœQt;+F2UDC›­Y;+F2; F2;4?A@hUF;d®-ž+z¡ d;BDC+e0UDW›QSR;~d&UN<ŒQtCBhgY>TQt>FB‚CEQt;Wk+eM>l¯ QSRT;Ygi;dU8CW W;FŒ:;nžpJ\HZu6¡PžN@„„;+FPBU8g UœQI>l¯wW>F2grCBDGŽh°’¤ g <t¡z¬ žŒ¡id;k+F;CA<2;ÃUDWš<;‡Wh<>&FSe]k>WdA@7kEQSUD>W£:(;BD>kUœQSeƒ>&¯QSR;Ãg ;4d&U8CWˆW;FŒ:;ZCA<z<2;A<z<;d]>&FŒQSRT>ldFV>grU8kCBBe y;zQN­r;;WrQSR;‘QSR@hg\yGlQSRUFd1d&U{UœQvC+WTd›­\F2UN<ŒQvžSBD>T­Y;+F*BDUgiUœQv>&¯6W>FVgrCB8Gh–§ g V<V¡z¬(žVŽ ¡PF;+BDCEQtU:;\d;B8C+e0UW <2;W<2>Fe£d&UN<SQtC‡BqBDCEQt;+Wk+e£>l¯‘QSRT;¸gr;4d&U8CWˆWT;+FV:;Ãk>lg~„hC+F;d ­YUœQSRKQSR;´@(BbWTC+FrW;+FV:&;¸CzQQSR;˜– QSR]d&U {lUœQ žp@„„;+FvBbUDgiUœQ6>l¯wWT>&F2grCBDG(§h°‚¢rg1<t¡E¬&žŒ–¡Pd;4k+F2;CA<;\UbWMCg›„BU’QN@(d;#>l¯QSR;#gi;dU8CW´<2;W<2>FeiWT;+FV:;nCAkzQSUD>lW „>AQt;+WQSUDCBp<ž†j mc•¡CEQ\QSRT; QSR@hg\y CWd QSRU F2d dU{UœQžŒBD> ­r;F˜BDUbgiUœQ0>¯1W>F2grCBDG´§ l n¡¬nCWd ža¢¡ CEyWT>&F2grCBU’QVU8;A<n>¯·QSRT; F2;k+FS@hUœQtgr;WAQq„CEQ8Qt;+FVWÃ>¯PQSR;1CEy(dA@(kzQS>F„>BbBDU8kUyF;4:UN<ng\@-<kB;1dA@F2UDW {ZW;;dBN; ;BD;kEQSF>&g\eT>&{FC+„lR e(° |·CkR0;‡B8U{UyB;\„CEQtUD;WAQ6­YCA<UDW¯S>&F2gi;d0>l¯wQSR; <SQN@(dTe1ye QSR;„R eh<2U8kU8CW CWTd <2UD{lWT;d Cnk>Wl<“;WAQ"¯S>&Ftg C¯Qt;+FwQSR;nkBbUDWU8kCBCWd W;z@F2>&„R e(<2UD>lBD>{Ukn;+oCgrUDWCEQVU‚>&Wh< ° H];4d&U8kCB6RUp<SQt>&FSeGwUDWkB‚@(dUDW{˜„F2UD>FRUp<SQt>&FSe>l¯qO_‰*†G-RCWdK<Vegr„ Qt>g <2GwCWd´QSRT;1k>&WTkB‚@<2U‚>lW˜>W´QSR; |6J\º<ŒQN@(d eM>l¯-QSR;rg ;4d&U8CW1W;+FV:&;ža<V¡P­Y;+F2;#F;+„>&FNQt;d›Qp>1>T@FPB8C+y>F2CQS>FŒe(°lmnBœQtR> @{R›QSR;#|6J\º<ŒQN@(de ­YCA<<2UgiUB8C+F¯S>FqCBbB6<Œ@y “;kEQ2<2G•d;EQtC+UDB8;d |J~ºdCEQtC#­Y;+F2;rCE:CU8BC+yB8;›¯S>Fq>&WBe]GD§ –Ã<Œ@y ;kEQ2<qžt—§ À˜¡ žVk> FtF2;A<V„>WdUDW {´Qp>椎´C+WTd¸¢`¦Ž˜kC<2;A<x>&¯·O_‰*†ÃC¯Œ¯t;kEQSUDW {´QSRT;›F2U{RAQqCWd˜BD;¯QP­~FaU8<ŒQtG-F2;A<t„;kEQSUœ:(;BDe ¡ ° ‹•>FQSR;1>AQSRT;+Fnž+§ À >¯kCA<“;<V¡2G6>&WBDe˜QSR;0k>WkB@<2UD>lWÃ>¯_QSR;›|6J~ <ŒQN@(d e´­YC <\C+:&C‡U8B8C4yB8; °•m <2;B8¯S^ CdgrUbWUN<ŒQt;+F;dˆ?A@(;<ŒQtUD>&WWTCUF2; ­YCA<\QSRT;‡W]giCUB8;dKQt>€;+C4k+Rš<S@ly “;kzQ“°}VW¯S>FVgrCEQtUD>WK­rC <ik>BbB8;kzQt;dˆ>W gi;dUk4C‡BZCWd <Œ@Ft{lUDkCBÃRUN<ŒQt>FŒe žV>Ty&;A<2UœQSeGÃdUC+y&;EQt;A<Ÿgr;BB8UœQN@<2G´QSR e`F2>lU‚d d&UN<2;4CT<;G˜{&eTW;k>lB‚>&{UDkCAB RUN<ŒQt>FŒeTG´­\F2UN<ŒQ RCWd QSF2Cz@g C4G „F2UD>FŸO*‰*†lGÃC+WTd @„l„;FšBDU8gYy g\@<2kE@(BD> <t«;B;zQtC‡B d&UN<2>F2d;+F“<V¡ŸCWd ;g\„BD>&egi;WAQ"žŒUDWdA@•<ŒQSFŒeTG>lk4kE@„CEQSUD>WGC+Wdrd;A<“kFaU „ QVUD>Wi>&¯hQtCA<t«h<6dA@FVUDW {\QSRT;„F2;k;dUDW{1¢#eT;C+F<V¡ ° ‰wR; F2;A<t„>&W<2;F2CzQt;·QS>QSR;?A@(;A<SQSUD>&WWTCUbF;_­rCA<I—¦ À™° @(C‡BDUœQSe k>WAQSF2>BP>¯QSR;0dCEQtC ­rC<#„;Fa¯S>F2gr;dK¯S>F´4§§£<S@ly “;kzQ2<#FC+Wd>lgrBDeˆ<“;B8;kEQt;4dKUbWϧ§  C‡Wd UDWAQt;+FV:U8;E­Y;d yešQt;BD;„lRT>&W;€¤”gr>WAQSR<ÃBCzQt;+Fz°‰w>ŠC‡<“<2; <<0QSR;ˆ„>h<<2UyU8BUœQSe >l¯´UDWkB@<2UD>lW yU8CA<G›CB8B . HAL author manuscript. . inserm-00256944, version 1 . .   

(19) . #. # . 

(20)  ! 

(21) . 

(22) ! # !. (. (. (.

(23) . (.

(24) HAL author manuscript. „CEQSUD;WQ2<UDWkB@(d;d›UDW\QSR;\<ŒQN@(dAeiUDWr§§ \­r;+F;k>lg\„CF2;d#­rU’QSR\„CEQtUD;WAQ2<6RC+:UDW{\@hWTd;+FV{>W;#<Œ@Ft{lU8kCB F2;BD;C <;\>&¯-QSRT;\gr;dUCW1WT;+FV:;\UDW §§ ^Œ§§Ž›@<2UDW{ QSR;\gr;4d&U8kCB-¯SUB8; <*>¯-QSR;nm#W`{h;+F“<XYC‡WTd1O*;‡WQt;+F2G ­~RUkR0„;+F2¯S>&F2gr;4d˜C+y> @Qq¦§ À >&¯*UDWAQt;+FS:;WAQtUD>Wh<¯S>&Fn<Œ@FV{UDkCBwF2;B8;C <2;i>l¯QSRT; g ;4d&U8CW˜W;FŒ:(; UDW QSR; H ruZF2;+{UD>&W(°. inserm-00256944, version 1.  %.(“N ‰wR;ÃkRC+F2CkEQt;FVUN<ŒQSU8kA<M>&¯#QSRT;˜{;‡W;F2CB„>„ @hBDCzQVUD>W]>l¯#QSRT;´H Yu F2;+{UD>lWK­Y;+F2;K;+o`QSF2CkEQt;d™¯NF2>lg QSR; ‹F2;WTk‡R j CEQtUD>WCB0}aW<ŒQtUœQN@Qt; >¯]† QtC QSUN<ŒQSU‚kT<£C‡WTdÁ|*k>W>g›U8k † QN@(dUD;A<]žŒ} j´† |6|P¡]k;Wl<Œ@<£>l¯Ÿ———h° }VWTk‡U8d;Wk4;#F2CEQt;A<6­r;F2;r;A<ŒQtUDg CzQt;d›ye1„CEQtUD;WAQvCWTd WT>TQ•ye ­~FaUN<SQtG"<>›QSRCEQv;4Ck+R „(CEQSU8;WAQw­rU’QSR yUbB8CEQt;F2CAB O*‰_†Ã­rCA<nF2;{C+F2d;dZCA<~>&WT;´kC<2; °w‰wR;0dCEQt;0>&¯*QSR; |6J~ <ŒQN@(dAe˜­YCA<@-<;d Qt>Zd;+¯SUbW; QSR;0dCEQt;0>&¯ dUDC+{W>h<2Up<q>¯*O*‰*†lGhy;k4CE@<“;#QSR;rdCEQt;r>&¯wQSR;r>Wl<;EQ*> ¯q<Veg›„ Qt>g <P­YC <UDgr„F2;kUN<“;r>&F*W>AQ·CE:&C‡UDB8C+yBN; ¯S>F6CEy> @Q•Ž§ À >&¯•kC<“;A<z° m{;^qC‡WTd´{;+WTdl;+F^a<V„;kUD¯VU8k CWW@(C‡B6UDWkUd;WTk;›F2CzQt;A<_­Y;+F2;ik>g\„ @Qt;d ­~UœQSR1QSR;›W@hg\y(;+Fx>&¯v„;+F<2>Wh< <Œ@(¯S¯V;+F2UDW {Š¯SF2>lg O*‰*† WT;+­rBeŠdUC{lWT>7<;d”dA@F2UbW{ QSRT;ˆe;C+F0@Wd;+FÃk4>&Wh<2UDd;+F2CzQSUD>&W C <ÃWA@(g ;F2CEQt> Fz° mr<<Œ@(g UDW{\QSRCzQhQSR;{;+W;F2CB„>&„ @(BDCEQtUD>W\F2;giC‡UDW;d <SQtCEyB8;GTQSRT;d;+W>g›UDWCEQt>F-­YCA<6C+Wr;<ŒQtUbgiCEQt;>¯hQSR; CE:&;+F2C+{;\WA@(g\y(;+Fv>&¯w„;+F“<2>W^Œe;CF<*>¯-QSR;\<“Cg ;nC+{;\CWTd›{(;‡WTd;+FvdA@FaUDW`{ QSR;\<“C‡gi;„;+F2UD>d›yC <2;di>lW QSR;Š——— }Nj´† |6| k4;+Wl<S@-< dCEQtC ° ÉwR;€C+{;4^VCd Œ@-<SQt;d F2;BDCEQtU:;ˆF2UN<V«<ÞN=_=q¡Ã>¯0O_‰*†ÁUDW ­Y>&Ft«UbW{ <Œ@y “;kEQ2<ndA@F2UDW {˜QSRT;Me&;C+Fn>¯dU8C+{W>h<2Up<Gk4>&g\„CF2;d´Qt>¸WT>&WT^p­r> Ft«UbW`{ˆ<S@ly “;kEQ2<‘dA@FaUDW`{ QSRT;Me&;C+Fn>l¯ dUDC+{W>h<2Up<G7­Y;+F2;rk>lg~„ @Qt;d´C4kk>F2d UDW {1Qt> ­~>&Ft«´UDW1{(;+W;+FC‡B"CWd Qt> ­~>&Ft«´UDWÃ<V„;kUD¯VU8k UDWdA@•<ŒQSFŒeCWd >kkE@„CQSUD>&W]k4CEQt;+{>FVUD;A<\@<2UDW{KQSR;´H£C‡WQt;BD^pXYC;Wh< ;Bgr;EQSRT>ld™¯S>Fr;CkRK{;WTd;+Fz°6‰IRT;ÃCEQNQNFVUy`@QtCEyBN; ¯NF2CkEQSUD>Wi>l¯-F2UN<V«1UDWM;4oT„>7<;d UDWdU:hU8dA@(CBN<*žVm‹h|

(25) À S¡-­rCA<vk>g\„ @Qt;dYQp>1;A<NQSUDg CzQt;xQSRT;‘„F2>„>FNQSUD>&Wi>l¯ kCA<;A<6>l¯•O*‰*† CQQSFVUy`@QtCEyB8;_QS>Y­~>FV«#@<tUDW {\QSR;¯S>lBDBD> ­rUW`{ ¯S>Fagn@hB8C®DL . . . (. (. *.  

(26) 

(27) 

(28) 

(29).  ! .

(30) . † QtC QSU8<ŒQtUDkCBhCWTC‡BDeh<“;A<•­r;+F;„;+F2¯S>&FVgY;d#@<2UbW{0† cv††¸Ž°œ§ <t>¯QN­rC+F; °. .

(31) ~)h%D“. HAL author manuscript inserm-00256944, version 1. m tQ >AQtC+Bx>&¯G¤l¥£kCA<“;A<Mža¥—£­Y>&gi;WGŽ –—€gr;Wh¬qgiC‡B8;®œ¯t;giC‡B8;ÃF2CEQtUD> `®±°¢¡2Gk>FŒF2;<V„>WdUbW`{ˆQt> GD¤ ––´­~FVUN<ŒQ2<xC‡¯S¯t;kEQt;d ye¸O_‰*†G ­r;F2; UDWkB@(d;d˜dA@F2UDW {´QSRT; Ž^Œe;CF„;+F2UD>dh° ‹•;E­ ;‡BDUD{U‚y(B8;›„(CEQSU8;WAQ2< F2;+¯@•<2;4dMQt>¸<tU{W QSR;rk>Wh<2;WAQv¯S>&F2grG-gYC‡UDWBbe0y;k4CE@-<; >¯PB8Ck+«>&¯wQtUbgi; °(‰IRT;+F2;#­YCT<*WT>´F2;k4>&F2d UDW`{˜>l¯ QSR;F;+¯@-<CBp<GTy`@QhQSR;;<ŒQSUDgiCEQt;{lU:&;‡W\yenQSR;#<;‡WQVUDWT;‡B(„R eh<2U8kUCWh<-­YCA<6B8;A<z<-QSRTC+W˜§ À™° O*‰_†0C¯S¯V;kzQt;d›QSR;#F2U{RAQtGBD;¯QtG>&Fy&>AQSR›­~F2Up<SQ2<*UDW1–§ ÀÃGhÀÃGC+Wd1Žl¥À >¯vkC <2;A<G7F;A<V„(;kEQtU:;Bbe(°&‹ >&F y> QSR0{;+Wd;+F<G<Veg›„ Qt>g <*­i;+F2;ikBC<z<2Uk1O*‰*†¸UDWÃC+y&>T@Q¥`§ À >¯*kC <2; <¯S>F_y&>TQSR1­~FaUN<SQ2<z°‰wR; giCUW |6J\ k+FVUœQt;+F2UDC_@<;d#Qt>rd;+¯ŒUDW;drO*‰*†Y­Y;+F2;Cd;BDC+eiUDW#QSR;_JnH™u >&¯hQSR;gi;dUCW\W;FŒ:;GCd;k+F;CA<2;UW QSR;ˆ<;+Wh<2>FŒe k>WdA@(kEQtUD>W :&;BD>lkUœQSeTG#CWTdšgr>F2;KF2C+F;+Be C™d;k+F2;4CA<2;™UDWˆQSR;€†j mc Cg\„lB8UœQN@(d; °*m\W UDWk+F2;C <;›>¯wQSR;›gY;d&U8CW w@(BbWTC+FB8CEQt;Wk+ed&UD¯V¯t;+F2;WTk;Y­YCA<qBD; <<q¯NF2;?A@7;‡WQy&;kCE@<;#QSRUp<qgi;CA<S@F2;#­rC < „;+FV¯S>F2gr;dr>WBberUDWikCA<;>l¯-grUB8drO*‰_†ižV‰6CEyBD; z¡z° ‰wR;?A@(CBDUœQŒe›k>&WQSF2>B>&¯hQSR;dCzQtC¯S>&F§§\F2C+WTd>&grBDe´<“;BD;4kEQt;d <Œ@y “;kEQ2<P<2RT>T­Y;d\W>rUbW¯S>F2giCEQSUD>WYyU8C < y;zQN­r;;W QSRT; <;B¯S^2Cdg›UDWUN<ŒQt;+F2;4dÁ?A@(;A<SQVU‚>&WWTC‡UDF2;ŸCWd”QSR;šUDWQt;+FŒ:U8;E­ F2;{C+F2dUbW`{Á{;WTdl;+FG C+{;Gi> F ;g\„BD>&egi;WAQ˜<SQtC QN@< °O*>&g~„C+F2Up<>&W >l¯MŽ—-™kC <;A<˜U8WkB@(d;d UDW §§  ­rUœQSR€QSRT;ˆ§§ ”CWdŸ§§lŽ gi;dUk4C‡B1¯SUB8; <Z>¯ QSRT;šmnW {;+F<˜XYCWdŠO*;‡WQt;+F™<VRT>T­Y;d QSRCEQCEy&>T@`Qä§ À >¯ QSRT;šk4CA<2; <Z>¯˜O*‰*† @Wd;FV{>lUDW {€<S@FV{;+FVeK­Y;+F2;˜W> QnUDd;WAQtUD¯VU8;dKye]> @F\W;EQN­~>FV«h°ji>ˆd UD¯S¯V;+F;‡WTk; ­iC<r¯S>T@(WdKy;EQN­Y;;W QSR;<2; <>T@Fk;A<qF2;+{C+F2dUDW {ÃC{h;G-{;Wd;+F2Gw;g\„BD>&egi;WAQ<SQtC QN@<G->FBDC <ŒQ_>lkkz@„C QSUD>Wh°‰wR;r„F2>„> FpQSUD>Wh< >¯<Œ@y “;kEQ2<w­Y>&FV«UDW {1UDW›QSRT;#giCWA@(¯VCkzQN@FVUDW {GhC+{F2U8kE@(BœQS@F2;Ghk>Wl<SQSFŒ@(kQSUD>&WTGhC+WTd´<2;+FV:U8k;#UDWdA@•<ŒQSFVUD; <vdUd W> Qvd UD¯V¯t;+FPy;EQN­Y;;W QSR;A<;#QN­r>˜<2> @F2k4;A<z°(‰IRT;Y„Ft>„>FpQ UD>lW0>¯yB@(;^Vk>lBDB8C+FP­Y>&FV«;zF<qC+WTd´BD> ­r;F_{FCd; ­~RUœQt;^Vk>BbB8C+F-­Y>FV«;+F<-­YCA<wUDW#QSRT;#<2Cgr;>F2d;+F">&¯•grC+{WUœQN@(d;‘¯S>F-y>AQSRi<2> @F2k;A< ° H];4d&U8kCBwCWTd¸<Œ@FV{U8kCBwRUN<ŒQt>FŒeCWd0;‡gr„BD>&egi;WAQq<ŒQtCEQ8@<P­r;F2;r>&WBDeÃC+:CU8BC+yB8;›¯S>FPQSR; ¥¢ ­Y>lgr;W C+WTd›Ž §rgr;W#­rRT> k>g\„B;zQt;d‘QSR;?A@(;<ŒQtUD>&W`WCUF2; °Hƒ;+W

(32) Ngr;CWrC+{;–Žh°’Žrž† J —h°‚¢¡e`F< wCWd#­Y>&gY;AW

(33) Ngr;CWŸC+{;K––°’—Ÿž† J —h°’Ž ¡re Fz< ´<Œ@(¯Œ¯t;+F2UDW { ¯SF2>g¿Oq‰_†€­Y;+F2;KF2;+B‚CEQVU:&;‡BDeŸe> @(W { žV‰6CEyB8;K¡z°·‹ ;E­ UDWkUd;WQ6kCA<;A<v>l¯wO*‰*†›­Y;+F2;nd&UDC{lWT>7<;d dA@F2UDW {i„F2;+{WCWTk4eMžŒÀ¡PC+WTd C+y> @Q6ŽŽÀ >&¯­r>gi;W C{;Ad y;zQN­r;;WŸ§^Œ–—šeT;C+F<RCd€@<“;d >F2C+Brk4>&WQSF2Ck;+„ QSU’:(;A<z°‰wR;™„F2;+:CB8;Wk;]>l¯M>Ty&;T<2U’QŒe žp¹*H™} •Žl§ . (. (.

(34) «{ SgN¡­YCA<q<2Ug UDB8C+FPy;zQN­r;;W1g ;WMC‡WTd›­r>gr;W1ž+¤ À˜¡ °‰IRT;#„F2;E:&CB;WTk;\>l¯6dUDC+y;EQt;<*g ;B8BbU’QN@-<6­rC < –ÀÃGl­rUœQSRT>T@`Qvd&UD¯S¯V;F2;Wk;\y;EQN­Y;;+W1{;Wd;F<z°‰RT;Y„F;E:CB8;Wk;\>l¯-QSR eTF2>lUDd1dUN<“;CA<“;‘­YC <*RUb{R0>WB‚e UW ­Y>&gr;WržŽ À˜¡z°‹h@FpQSRT;+F2G§ À >¯-gi;+WrCWTd›Ž§ À >¯h­i>gr;W›RTCdr>Ty&;A<2UœQSeGd&U8C+y;zQt;A<6gr;BBU’QN@<2GC‡WTd S>F QSR e`F2>UDd dUN<“;CA<2;4G&QSR;nC+{;^VC4d Œ@•<ŒQt;4d›„F2;E:&CBD;Wk;#UDWk+F2;C <2UDW {0<2UD{lWU8¯VU8kCWAQtB‚eiUDW1k4CT<;#>¯ @(W;gr„BD>&egi;WAQ žVŽl¥À :h< °h¢ÀK¬ c  §h°œ§§-z¡“°q‰IRT;£„F2;z:CB8;‡Wk4;ˆ>¯ QSR;A<;ˆdUN<2>F2d;+F<d UDd WT>TQi:C+FVe”<2UD{WUD¯VU8kCWAQtBbe Ckk4>&F2d UDW`{YQp>›UDWdA@<SQSFVer>F•>lkkz@„CEQSUD>WrkCEQt;+{> FtUD; <z° ‰wR;KkFŒ@(d;KC+:;F2C+{;šz^Vgr>WAQSR€UDWkU8d;‡WTk;K>¯ O*‰*†Ÿ>T:&;+F›QSRT;KŽ^ŒeT;C+Fi„;+F2UD>ld™­rCA< °±–Ÿ¯S>FKGD§§§ „;+F<>&WT^Œe;4C+F<6UDWY­Y>lgi;WrCWdr§h°’¤›¯S>FGD§§§Y„;F<t>&WT^te&;C+F<6UDWrgi;‡W(° ‰6R;UbWkU8d;Wk;>¯-O*‰*† UDWr§§ G §§ŽG-CWd1§§ – ­YC <r°‚¢`G*°’¤G-C+WTd£° C+Wd0§h°’¤G-§h°’¦ G•C+Wd0§h°’¤´¯S>&FrGD§§§1„;+F<2>W^Ne;C+F“<UDW1­r>lgY;AW C+WTd g ;WTG#F2; <V„;kzQVU:;BDeh°x‰R;]dl;4k+F2;CA<“;]>¯´UDWkU8d;‡Wk4;ˆ> yh<;+FV:;d ¯S>F ­Y>lgr;W UbW §§ – ­rC<ÃW> Q <ŒQtCQSUN<ŒQtUDkCBBDe˜<2UD{WUb¯tUkCWAQvCWd›y> QSR\QSR;\grCB8;®œ¯t;‡giCB8;#F“CEQSUD>0C+Wd›QSRT;#„F2>„>FpQSU‚>&WM>&¯-­Y>&Ft«UbW`{˜<Œ@y “;kEQ2< dUDd WT>AQw:C+FVe0<2UD{lWUD¯VU8kCWAQtBe1dA@F2UDW{ QSR;n„;+F2UD>ldh°}VWTkUDdl;Wk;\UbWTk+F2;C <;d›­rUœQtR1C+{;~žpc K§h°’§§-“¡PUDW y> QSR {;+WTd;+F<2Gh­rRCzQt;E:(;+FPQSR;r;gr„lBD>egi;WAQq<ŒQtCEQN@<qžV‰6CEyBD;r¡z°h‰wR;\„F2>„> FNQSUD>W0>l¯w­r>FV«UDW {K<S@ly “;kzQ2<P­rC < RUD{lRT;+F*UDW „(CEQSU8;‡WQ2<­rU’QSR1O*‰_† QSRTC+W1UDW QSR;#{;W;F2CB „>„ @(BDCEQtUD>&WM>&¯-QSRT;#H Yu]F;+{lU‚>lW1žV—§ À :h< w¥zÀ UDWrg ;WrCWTdM¥`§ ÀÄ:< ° ¤¤ À UDW#­Y>gr;W ¡z°`‰IRT;k+FŒ@(d;gi;C+WrUDWk‡U8d;Wk4;F2CEQt;>¯-O*‰*†›„;FGD§§§#„;+F<>&WT^ e;4C+F<­YCA<*RU{R;+FPUDWM;‡gr„BD>&e&;d›„;+F“<2>Wh<IQSRTCW Cgr>W { QSR>h<2;@W;gr„BD>&e;4d UbWrQSR;‘e&;C+FP>¯wdU8C{lWT>7<2UN<

(35) °’¤—K:h< x§h°¥–ˆUDWK­Y>lgr;W]CWd]§h°œ¤-1:h< °P§h°’Ž§ˆUDW™gi;W]žpy> QSRK c  §h°œ§§-z¡ a°6‰wR;¸B‚CEQNQt;+FikCQt;+{>FVe k>g\„F2UN<2;d y> QSR´<S@ly “;kEQ2<6­rR>1RC4d WT;4:(;F­r>FV«;dGg CUDWBbe ­Y>lgr;WTG CWTd›@hWT;‡gr„BD>&e&;d <S@ly “;kzQ2<*UW QSR;€eT;ACFK>¯d&U8C+{W>h<2UN<z°\‰wR; C+{;^VC4d V@<ŒQt;4d =*= UDWº;g\„BD>&e;4d <Œ@y “;kEQ2<Zk>lg~„C+F2;d ­rUœQtR QSR>h<2; @W;gr„BD>&e;4d UDW1QSR;›e&;C+F>¯*dU8C+{lWT>7<2U8<_­YC < °’—

(36) N—l¢4À OP}2G*°œ¤`^Œ°’Ž PUbW1­Y>lgr;W˜CWdˆ°’Ž

(37) N—l¢À OP}VG §h°’—^+°’— -UDWrgr;Wh° ‰wR;˜;gr„lB‚>&e;dˆ<S@ly “;kEQ2<i<Œ@(¯Œ¯t;+F2UDW{ˆ¯NF2>g O*‰_†K­Y;+F2;¸gYC‡UDWBbe]BD> ­Y;+F\{F2Cd;1­rRUœQt;^Vk4>lBDBCF#­r>FV«;+F“< C+WTdƒyB@(;^tk>&BDB8C+Fr­r>FV«;+F<iCWdˆF2CF2;B‚e]y(;BD>lW`{;d£QS>]gr>&F;¸?A@(CB8U¯VU8;d]>lk4kE@„CEQtUD>&W]k4CEQt;+{>FVUD; <z°v‰IR; ;Eo&kA;<<6>l¯F2UN<V«i>¯-O*‰*†Y­YCA<P<SQtCEQSUN<ŒQSU8kCBBDe1<2UD{lWUD¯VU8kCWAQ•¯t>&F•g CB8;CWdr¯S;‡giCB8;xyB@(;^tk>lBDB8C+F-­r>FV«;+F“<6C+Wd ¯t;‡giCB8;´BD> ­r;F#{F2C4d; <;+FV:Uk4;A<2G_<CB; <GPCWdKkB8;+F2UDkCB­~RUœQt;^Vk>BbB8C+F­Y>&FV«;F<~žŒ‰6CEyB8;´Ž ¡ °-}VWZk>WAQSF2CA<NQtG . . HAL author manuscript. . inserm-00256944, version 1. (. (. (. . (. (. (.

(38) HAL author manuscript inserm-00256944, version 1. R UD{lRT;+FrB8;4:&;B>kkE@„CzQVUD>W™kCEQt;{> FVUD; <2G<Œ@(kR]CA<\­Y>lgi;+W]k+FC‡¯Q2<^\CWdˆ<“CB8;A<V„;F<2>Wh<rCWd]g CWTC+{;+F<G Qt;k+R`WU8k‡U8CWh<2GC+WTd1C <<2>kU8CEQt;#„Ft>&¯S;A<z<2U‚>lWCBN<*>l¯wy> QSR {;Wd;+F<Gl­r;+F;\CA<z<2>kUDCEQt;d›­YUœQSR1C\BD> ­r;FPF2U<V«0>l¯ O*‰_†°}tWˆQt;+FVg1<>&¯1UDWdA@<SQSFeTG‘­Y>FV«UDW {”UDW C+{F2Ukz@hBœQS@F2;]žŒ¯S>F ­Y>&gY;‡W`¡2G#giCWA@(¯SCkEQN@FVUDW { ž¯S>F1y>AQSR {;+WTd;+F<V¡Gk>Wl<SQSFŒ@(kEQSUD>WÞV¯S>Fg ;W`¡nC+WdG-Qt>KC BD;<z<2;+Fn;Eo`Qt;+WAQtGP<2;FŒ:U8k; UDWdA@<SQSFaU‚;A<nžV¯S>&F­Y>gr;W ¡­YC&< CA<“<2>k‡U‚CEQt;d£­rU’QSR€CWƒ;4o&k; <<iF2Up<t«Ÿ>¯rO*‰_†°P}VWƒk>WAQSFtCA<ŒQtG_­~> FV«UDW`{šUDWˆQSRT;£<;+FV:Uk4;KUbWdA@<SQSFVU8;A<r­rC < CA<“<2>k‡U‚CEQt;dK­rUœQSRƒC¸BD> ­r;F›F2UN<V«ƒ>l¯~O*‰_†€¯S>F gr;WƒžV‰6CEyB8; –¡ °Pm#gr>W {™­r>lgY;‡WTG·QSRUN<iBCzQNQt;+F1<2;kEQp> F giCUbWBbe UDW :>B‚:(;4dšyB‚@(;4^Vk>lBDB8C+F0CWdŸBD>T­›;+F1{F2Cd;¸­rRU’Qt;^Vk>lBDB8C+F ­Y>&Ft«;+F<0ža¥–À¡¬Cgr>W { gi;WGnU‚Q UDW :>lB:(;d1yBœ@;4^Vk>BbB8C+FP­Y>&Ft«;+F<qžŒ–— À0¡qC+Wd0CB<2>˜C\F2;BCzQSU‚:&;BbeBCFV{;\„;+F2k;+WQtC+{;ržŒ— À˜¡*>¯v?A@(C‡BDU8¯VU8;Ad ­~RUœQt;^Vk>BbB8C+F-­Y>FV«;+F<6CWd\„FV>¯S;A<z<2UD>WCBN<z° ‰wR;nCEQNQNFVUy`@QtCEyB8;Y¯NFCkEQtUD>&WižVm‹h|P¡vUbWi;gr„lB‚>&e;dr„;+F<>&W<2G&­rRU8kRrF2;+„F2;<“;‡WQ2<wQSR;„F2>&„T>&FNQSUD>Wi>&¯"O_‰q† <V„;4k‡UD¯VU8kCBDBbeZCEQNQ FVUy @QtCEyB8;›Qp>­Y> FV«ÃCgr>W { kC <2;A<n>kkE@FtFVUDW {ÃUDW´QSR;Y­Y>&Ft«UbW`{Ä>&„ @(BDCEQtUD>W ­YCA<–¦ À žV—l¢À O·}GwŽ— ^a¢–¡q¯S>&F*­~>&gr;WCWd˜k> @(BDd˜W> QPy;ik> gr„ @Qt;d˜¯S>&Fqgr;Wh°‰wR; m‹h| >&¯*O*‰*†˜F2;CkRT;Ad :CB@(; <n> :;+Fn¤§ À ¯S>&F¯S;giCB8;1C‡WTd¸giCB8;MyB@7;^Vk>BDBCF‘­Y>&Ft«;+F<nC+WTd¸¯S;giCB;1BD> ­r;F{F2Cd;´<2;F:U8k; <G <2CB8;A<G-CWd0kB;FaU‚kCB ­rRUœQt;4^Vk>lBDB8C+FP­r>FV«;+F“<qžŒ‰6CEyB8;rŽ ¡z°}VW Qt;+FVg <q>¯PUDWdA@•<ŒQSFŒeTG7QSRT;\m‘‹h|š>&¯vO*‰_†1­rC < RUD{lRT;+FUDW0C+{F2U8kE@(BœQN@F2;ržV¯S>&FP­Y>&gY;‡W`¡qC+Wd0k>Wh<ŒQSFŒ@(kQSUD>W´UDWdA@<ŒQSFVe ž¯S>F*gr;W ¡PQSRCW0UDW˜giC‡W@h¯SCkEQN@FtUbW{ žŒ¯S>F-y>AQSR\{;Wd;+F<t¡6CWd#QSR;#<;+FŒ:U8k;UbWdA@<SQSFVU8;A<6žV¯S>F-­~>&gr;W`¡6žV‰CzyB;–¡ ° ~

(39) 4) “8. ‰wR;£<SQSF2;+W`{ QSR]>&¯QSRUN<˜<ŒQN@(dAeƒBU8;A<1UDW™QSR;ÃUbWkB@•<2UD>lWƒ>&¯\UDWkU8d;WAQYO_‰*†€UDW£QSRT;˜{;‡WT;+F2CB„>„ @BCzQSUD>lW F2;+„> FNQt;d›ye CM<;WAQtUbWT;B<Œ@FS:(;‡UDB8BCWk;\WT;EQN­r>FV«M>&¯w„R e<2U8k‡U8CWl<qk4>T:&;+F2UbW`{˜C\B8C+FV{;~C+F2;Cr>¯IQSRT;#F2;+{UD>lW(° O*CA<2;]d;¯ŒUDWUœQtUD>lW C+{F2;;4dƒ­YUœQVR]QSR;™k>&Wh<;Wl<Œ@•<0d;¯VUDWUœQVU‚>lWl<¯S>&F0;+„UDd;g›U‚>lBD>{lU8kCB <S@F:&;UBB8CWk4;ˆ>l¯ O*‰_† »V¾ L[vC+WTd QS>>«ÃUbWQt>KCk4k+> @WAQPQSRT; „ @yBDUp<2R;4d F;k>g gi;WdCEQtUD>Wl< ¼ ¯S>FW;E@F2>„R eh<2U‚>lBD>{lU8k´<ŒQN@(dUD; < >¯O*‰*†° W;1BU8g›U’Q2CEQSU‚>&WÃ>¯·QSRT;´<ŒQN@(d e´­YC <QSR;1B8Ck+« >&¯q;+oRCE@<SQVU:&;‡WT; <<n>l¯PQSRT;´<“;‡WQSUDW;‡B6W;EQN­Y> FV« ­~RUkR˜B8;d1Qt>¸CW @WTd;+F2;A<SQVUDgiCEQtUD>&W>¯QSR; UDWkU8d;‡WTk; >¯*O*‰_†°‰wR; BDCk«Ã>l¯*;+oRCz@<ŒQtU‚:&;W;A<z<>¯QSR; W;zQN­r>FV«k+> @BDd y&;›;+oT„lB8CUDW;d yedU¯V¯t;+F2;WAQv¯SCkEQS>F< °l‰wR;rWA@(g\y(;+Fq>&¯6„;+F<>&Wh<<S@h¯V¯t;+F2UDW {˜¯SF2>lg O*‰*† . ).

(40) ­rUœQSRT>T@Qn@Wd;FV{>UDW {™|J~ <ŒQN@(dUD; <iUp<\@(W «W> ­~W£y`@lQ~„ Ft>Ty&C+yB‚eƒRUD{lR(° }ŒQ~grUD{lRQ#y&; „>h<<2UyB8;´QSRCEQ ;g\„BD>&e;4dš<Œ@y “;kEQ2<\­Y>T@BDd™y;¸gY>&F2;ÃBUD«;Bbe™Qt>£@WTd;+FV{>K|J~ <SQN@(d UD;A<M>&F1<Œ@Ft{UDkC‡B*F2;B8;CA<2;´QSRTCAW @W;gr„BD>&e;4d <S@ly “;kEQ2< °j ;+:;FŒQSR;B8;A<z<2GlQSRUN<<>T@Fk;\>l¯wyU8CT<*UN<*„F2> yC+yBDe0BD>T­ UbW1‹F2CWTkA;4G"<2UDWk;rgr>h<ŒQ >¯7QSRT;k>h<ŒQ2<6C+F;„C+UDdYyenQSR;\†>kUDCB-†;kE@F2UœQSeTGT­YRCEQt;E:&;+F-QSR;;g\„BD>&egi;WAQ6<SQtC QN@<6>¯hQSR;„CEQSU‚;‡WQ2<z° }VW <2>gi;K„CEQtUD;WAQ2<2G\<Œ@Ft{lUDk4C‡BnF2;B8;C <2;™>l¯\QSRT;£gi;dU8C‡WŸW;+FS:;¸­YCT<M„;+F2¯S>&F2gr;dˆ­rU’QVRT>T@Qr|6J\ <pQN@(d U8; < dA@F2UDW {˜QSR; „F2;4k;dUbW{ Ž¤¸gr>WAQSRl< °7XY> ­r;E:&;+F2G-QSR;+eZg UD{RAQqRC+:;0CWÃ;B8;AkzQSFV>d UDC+{W>h<ŒQSU8k1;+:CB@(CEQtUD>lW ;C+F2BDU8;+Fz°‹•>&F0QSRCEQ0F2;4CA<2>WG1<Œ@FV{UDk4C‡BMdCEQtCŸC+Wd |6J\ <SQN@(d UD; <ZC+F2;€W> Q;CA<Ve Qt>Ák4>&g\„CF2;ŸCEQ1QSR; UDWd&U:(U8dA@(C‡BB8;+:(;‡B °l†>g ;„;4>&„B8;BbU:(UDW{ UDW#QSR;H ru C‡F;C‘grUD{RAQ•RCE:&;_@hWTd;+FV{>W;;B8;kEQSF2>d UDC+{W>h<ŒQSU8k <ŒQN@(d U‚;T<6UDWiCW CF2;CW> Qwk> :;+F2;4dYye\QSRT;‘WT;EQN­r>FV«ižŒ„`FV>Ay&C4yBDeiB; <“<IQSRTCW ¢À >&¯";BUD{lUyB8;nkC <2;A<t¡z° m ¯t;+­ ;BDUb{UyhB8;1kC <;A<F2;¯N@<2;d´Qt>£<tU{W´QSR;1k>Wh<2;WQ¯S>F2g ¯S>F\<2;z:;+F2CB6F2;CA<>&Wh<GgrCUDWlBDeZ¯S>&FnBDCk+«Z>l¯PQSUDgi;° ‰wR;BDCk+«i>&¯•;+oRCE@<SQVU:&;‡WT; <<-­YC <6CBp<> dA@(;PQS>#QSR;_@WT;?A@(CB„C+FŒQSUDkUD„hCzQSUD>&WY>l¯hQSR;#<2;WAQtUbWT;Bl„R eh<2U8kU8C‡W< > :;+FQSRT;›QSR F2;;4^teT;C+F„;+F2UD>dGgrCUDWBbeZUDWK§§ –° W;1„R eh<2U8kU8C‡WZW> QSUD¯ŒU8;d¸:&;+FVeK¯t;E­ kAC<2; <n> :;+FQSR; QSR F;;£eT;C+F< CWd CWT>TQSRT;+F˜BD;¯Q QSRT;ˆW;zQN­r>FV« UDWŸ§§Ž ¯S>&F0„;+F<>&WTC‡BnF2;C<2>Wh°}2W CddUœQVU‚>lWG›<>&gi; ;BDUb{UyhB8;nkCA<2; <w­r;F2;#W> QwUDWkB@(d;d›y;4kACz@<2;n>l¯ QtUDg ;n„lF2;<<Œ@F; °h† @(k+R F;CA<2>Wh<w­r;F2;#CBN<2> F;+„>&FNQt;d UDW C <2U8g U8BCF#<“;WAQSUDW;BWT;EQN­Y>&FV«UbW1QSR;YM†lmr° x‰IRT; B8Ck+«Z>¯q;4oRTCE@<ŒQtU:;W; <“<n>&¯PQSRT; W;EQN­r> Ft«Ã;Eo„B8CUbW< QSR;\F2;BCzQSU‚:(;BeBD>T­ ;A<ŒQtUDg CzQt;›>¯PUDWkU8d;Wk;r>l¯vO*‰_†0UDW QSRUp<*{;WT;+F2CB„>&„ @(BDCEQtUD>W0k>&g~„hC+F;dMQp>›QSR>h<2; F2;k4;+WAQtBe F2;+„>FNQt;d UDW QSR; {;‡WT;+F2CB „>&„ @(BDCEQtUD>Wl< >l¯ O*C‡WQt;+FŒy`@Fe CWd †lU‚;‡WWC @<2UbW{ ;BD;kEQSF>&„R e<2UD>lB‚>&{U8kCB6d;‡¯SUDWlU’QVUD>W0>l¯PO*‰*†°±s ¾ XY>T­Y;E:&;‡FG W>Ã<2U{lWUD¯VU8kCWAQ·d&UD¯S¯V;F2;Wk; <P­Y;+F2;r>Ty<;+FV:;d y;zQN­r;;Wi„CEQSU8;‡WQ2<*UDWkB@(d;d UDW QSRT;›<ŒQN@(d eMC‡WTd›QSR>h<2;‘QSF;CEQt;d´<S@FV{UDkCBBDe1F2;{C+F2dUbW{0C{;Gh{;‡WTd;+F*CWd B8C <ŒQ >lk4kE@„C QSU‚>&W(°1O*>&W<2;?A@7;WAQSBeG˜;+:&;‡W QSRT>T@{R QSR;ŠUbWTkUd;WTk;Á>¯™O*‰_†º­rCA<™@WTd;+F2;A<SQVUDgiCEQt;dG ;A<SQSUbgiCEQt;<>l¯vF2;BCzQVU:;rF2Up<t«Z>&¯qO*‰_†ÃC4kk>F2d UDW {˜Qt>˜{;EWTd;+F2GwC+{;iC‡WTdÃ;‡gr„BD>&eTg ;WQ<ŒQtCEQN@<*­Y>T@BDd´y(; ;EoT„;AkzQt;d‘QS>\y;_@WyUC <;dh° ‰wR; gi;EQSR>d>&B‚>&{e ­Y; @•<2;d dU8d W>AQCBDBD> ­ „F“;kUN<2; CA<“<“;A<z<2gi;‡WQ>&¯”yUD>lgi;kRTC‡WU8kCB C‡Wd „h<VekRT>7<>lk+U‚C‡B*F2UN<V«]¯VC4kEQt> F<\¯S>FrO*‰*† °6OP>Wl<;?A@(;WAQtBeGPQSR;˜UDWdA@<SQSFe žV>FQSR;>lkkz@„CEQSUD>W™kCEQt;{>&FŒe`¡ ­YCA<@<2;dZCT<~C  „F2> oe ™¯S>F~;Eo„>h<Œ@F2; QS>ÃFVUN<V«™¯SCkzQt> F<\¯S>F\O*‰*†h°DLŒLPJn@(;›QS> QSRT; <2gYC‡B8B*WA@(gYy(;F\>l¯ (. (. HAL author manuscript inserm-00256944, version 1. ). . .

(41) @W;gr„BD>&e;4d „CEQtUD;WAQ2<GlQSR;\„F2;kUN<2UD>W0>l¯IQSRT;r;A<ŒQSUDgiCEQt; <q>&¯wQSR;rC+{;4^VCd Œ@-<SQt;d =_= C+Wd0m‹h| >¯PO*‰*† UDWi;‡g~„lBD>e;d <Œ@y “;kEQ2<-­YCA<wF2;BDCEQtU:;BbeYBD>T­M° . (. HAL author manuscript inserm-00256944, version 1. rm <´„F;4:U‚>T@<2BDe F;+„>&FSQt;dšUDWŸ„>&„ @(BDCEQtUD>W^ŒyC<2;dÁ<SQN@(d U; <G‘QSR;ˆUDWkU8d;Wk;]>l¯0O*‰_†Ÿ­rCA<RUD{lRT;+F˜UW ­Y>&gr;W0CWd1UDWk+F2;C<2;d ­rUœQSR0C+{;\¯S>FPy> QSR {;+WTd;+F<z° s ¾ ‹•;E­Y;+FQSRTCW À >l¯-­Y>lgr;W1UDWkB@(d;d UDW QSR; <ŒQN@(dAe~­r;+F;„F2;+{WCWAQ"CWd#QSR;„F>&„>FpQSU‚>&Wr>¯7­Y>lgr;W\@<2UDW {M>&F2CBhk>WAQSFCk;+„ QSUD>W#­iC<_<2U8grUB8C+FwQS>YQSRTCEQ > yh<2;FŒ:;dŸUDWˆQSR;K{;W;F2CB„>&„ @(BDCEQtUD>Wh°DLs1‰wR;K„F;E:(CB;WTk;™>l¯rdU8C4y&;EQt;A<1gi;BB8UœQN@<0UDW€„CEQtUD;WAQ2<r­rC < QN­~UDk;rCA<qRUb{R›QSRTCEQvUbW QSRT;#{(;+W;+F2CB„>&„ @(BDCEQtUD>W1>l¯-QSRT; <2Cgi;›C{;GNLs*C+WTdMQSRUN<qk>W¯ŒUDF2g1<PQSR;\¯VUDWdUbW{< >¯›<S@FV{lU8kCB\<;+F2U;<z°DL ¼ O*>&W<2Ud;FaUDW`{ˆQSRCEQ~W>]F2;+¯S;+F2;Wk;ÃdCEQtCK<ŒQtC+WTdC+F2dU ;d€¯S>F1<2;+oƒCWd]C+{; ­Y;+F2; CE:&C‡U8B8C4yB8;¯S>&F-QSRT;{;+W;F2CB„>&„ @(BDCEQtUD>Wr>&¯hQSRT;_H]CUDW; ”uv>lUF2;F;+{lU‚>&Wrk4>&WTk;+F2WUDW{ dUDC+y(;EQt;A<6gr;B8BbU’QN@-<G ­Y;1k>T@B‚d¸W> Qxk+>g\„ @Qt;›QSRT; F2;BDCEQtU‚:&; F2Up<t«Z>l¯qO_‰*†ZCkk>F2d UDW {˜Qt>Kd U‚C4y&;EQt;A< ° y; <2UœQSe´­›CA<QN­rUDk4;1C&< ¯NF2;?A@7;WAQICA<PUDW\QSR;{;W;+F2CB„>&„ @(BDCEQtUD>Wi>l¯ QSRT;‘F2;{lUD>W1C{;d¸¢\eT;C+F“<P>F6gr>&F;#C+WTdYQSRUN<vC+{F2;; <w­rUœQtR <Œ@FS:;+eh<*UDW QSR;n{;‡WT;+F2CB„>&„ @(BDCEQtUD>Wh° [h\W¯S>FŒQN@WTCEQt;+BeTG7QSR;~CE:CUB8C+yB8;\dCEQtC\>W1> y;<2UœQŒeMUDW›QSR;#{;+W;F2CAB „>„ @BDCEQtUD>&W0>¯IQSRUN<xC+F2;Crd>´WT>TQ·C+BDBD> ­ÄgY>&F2;\„F2;4k‡UN<“;iC+WCB‚e(<UN<x>&¯wQSR;rF2;B8CEQSU:(;YF>&BD;i>&¯·>Ty&;A<2UœQSeC‡Wd >kkE@„CQSUD>&W]>W¸QSRT;´F2UN<V«]>l¯~O*‰_†°wm#B’QVRT>T@{RÃQSR;K<ŒQN@(d e k>&W¯tUbF2gi;d¸QSRT;¸k4>l^V;zoUp<SQt;+Wk4;˜>l¯ng ;4d&U8kCAB k>WdUœQtUD>&W<6«lWT>T­~W\Qt> UbWTk+F2;C<“;xQSRT;‘F2U<t«1>l¯"O_‰*†1UDW <“>gr;„CEQtUD;WAQ2<2GhUœQICB<2>´<tR> ­r;d\QSRCEQICEy> @ QI¦§ À >¯ ¯t;‡giCB8;™CWd ¥`§ À >l¯ giCB8;K„CEQtUD;WAQ2<0dU8dšW> Q0<Œ@T¯Œ¯t;+F0¯ŒF2>g C‡W eš>l¯\QSR;g1°q‰RA@<G#gr>h<ŒQMkCA<;&< >kkE@FVF2;4dˆUDW€F2;B8CEQSU:(;‡BeŸeT>T@(W { C‡WTdšRT;CBœQVR eƒ­r>FV«UDW{ˆ­Y>&gi;W€CWTdšgi;Wh°*‰wRUp< ;+„lU8d;g U‚>lBD>{lU8kCB „F2>¯ŒUDB8;\>¯6O*‰_†1UDW›QSRUN<P{;WT;+F2CBh„>„ @hBDCzQVUD>Wid&U8¯V¯t;+F<vd&FCA<ŒQSUDk4C‡B8BbeM¯ŒF2>g QSRT;YRUN<SQt>&FVU‚kCBkBUDWlU8kCB„F2>¯ŒU8BN; >¯˜O*‰*†lGiCkk>F2d UDW {”QS>”­\RU8kRŠO*‰_†>lkkz@F<ÃgrCUDWlBDe UDW grU8dd&B8;^tC+{h;4d ­Y>&gi;W <Œ@(¯S¯V;+F2UDW{ ¯NF2>hg R>F2gr>WCB•d&UN<2>F2d;+F“<z° »V¾ L ¼ m <S@yh<SQtC‡WQSUDCBwWA@(g\y(;+Fq>&¯vkCA<2;A<q>kkE@FtF2;d1UbW˜<S@ly “;kzQ2<BD; <“<PQSRCW0Ž§ eT;C+F< >¯ C{;G£FC+UN<2UbW{ k>Wk4;+FVWh<ŠCEy&>T@QƒQSR;Ą>AQt;WAQSU8CBˆBD>W { Qt;+FVg ;¯S¯V;kzQ2<Š>&¯ O*‰*† WT>AQ >&WBe >lW g\@<“kE@(BD>7<t«;B;zQtC‡BR;4C‡B’QVR#y`@Q"C‡B8<2> >Wr;+g~„lBD>eg ;WQ“° ‰wRUp<<ŒQN@(d e <2RT>T­i<›QSRTCEQigr>h<ŒQikC<2;A<0>¯iO*‰_†ŸUDWˆQSR;¸{;W;F2CB„>&„ @(BDCEQtUD>WŸ>lk4kE@FVF2;d€UDW™­r>FV«UbW{ <Œ@y “;kEQ2<M>&¯\y&>TQSR]{;+Wd;+F<G„C+FŒQSUDkz@hB8C+F2Bbe UbW€yB@(;^Vk4>&B8BCF›­Y>&FV«;F<1CWd€BD> ­i;+F {FCd; ­rRU’Qt;^Vk>lBDB8C+F . *. ). (. . (. .

(42) ­Y>&FV«;F<z°A|q<ŒQSUDgiCEQt;A<·>&¯-QSRT;#=_= >l¯6O*‰*† ­r;+F;~y&;EQN­Y;A;WK°¢iCWd ˜UDW ­Y>&FV«UDW`{¸<S@ly “;kEQ2<*UDW1{;W;F2CAB C+WTdˆŽKQt>ˆ–]UbW]yBœ@;4^Vk>BbB8C+F\­Y>&Ft«;+F<z°v‰IRT;A<2;˜F2; <S@hBœQ2<MC+F2;Ãk>Wl<2UN<SQt;+WAQn­rUœQSRƒ;+„UDdl;grUD>lB‚>&{U8k£<ŒQN@(dUD; < <VRT>T­YUbW`{ÁRUD{R;+FUbWkU8d;Wk;™F2CEQt;<˜>¯1O*‰_†”UDW”k4;+FŒQtC+UDW”>kkE@„CzQSUD>&WCB\{F>T@„h<G#giC‡UDWBDe”UDWdA@-<SQSFVU8CAB ­Y>&FV«;F<z° ¾ »t¾ L \m#BDB*QSR;¸giCUDWˆUDWdA@<SQSFaU‚;A<\­r;F2;¸UDW :>Bb:;4dG;Eo(k;„ Q\¯S>F1<2;+FŒ:U8k;ÃUDWdA@•<ŒQSFVUD; <i¯S>&Frgr;WTG ­rUœQSR1=*=ŠF2CW {UDW{¸¯NF>lg °¥ Qp>˜Žh°’§l°lX~> ­r;E:&;+F2G =*=Šg UD{RAQ*RTC+:;›y;4;‡W1@(Wd;+F2;<ŒQtUbgiCEQt;4d y;k4CE@-<; >l¯ QSR; 4dUB@QVU‚>&W n>l¯ :&;+FVei;+o„>h<2;d <V„;4k‡U8¯VU8kCkEQtU:UœQVU8;A<*<V@(k+RYCT<6¯S>>ld\„Ft>lk4;A<<2UDW {MCWdrkB;4C‡WUDW{GCgr>&W{ B8; <<iRUb{RBbe ;+o„>h<2;d]>kkE@„CEQSUD>Wh<z° ¾ L i‰wR;˜F2;A<S@hB’Q<0<Œ@„„>FpQQSRT;Ã>&„UDWUD>lWKQSRCzQr>kkE@„CEQSU‚>&WTC‡BqF2Up<2« ¯tCkEQt>F<\¯S>FrO*‰_†]C+F;˜k+>Wk4;‡WQSF2CQt;dKUDW¸­Y>&FV«;F<rgr>h<ŒQ~;EoT„>7<;d¸QS>™F2;+„;QSUœQtU‚:&;˜gr>&:;gi;WAQ2<YC‡WTd S>F R;4C4:e „lR e(<2UkCB ­Y>&FV«BD>Cdh°r‰wR; F2U<V« >¯ZO_‰*† CA<z<2>kUDCEQt;dÁ­~UœQSRÁ­Y>&FV«ºUDWÁQSRT;Á<2;+FŒ:U8k;Á<2;4kEQt>&F d F2CA<SQSUDkCBBDeMd&U8¯Œ¯t;+F2;d›y&;EQN­Y;;W›{;WTd;+F<z°T‰IRUN<6„F2> yC+yBbeiF2;¯SB;kEQQSRT;‘{;Wd;FPdU:Up<2U‚>lWi>l¯ ­Y>&Ft« UDW\QSRUŒ< <2;4kEQt> F2G¸<tUbWTk;Ágr><ŒQ >&¯ÃQSR; ­r>gr;W y;BD>W {;d Qt> QN­~>ÄRU{RºF2UN<V« BD> ­ ?A@(CBU¯SU8;dÄ>kkE@„CEQSUD>W kCEQt;{>FVUD; <2G ­\RT;+F2;C<giCW ergi;W\y;BD>lW`{;d#Qt>YRU {lR\{FCd;>lk4kE@„C QSU‚>&Wh<-­YUœQSRrCBD>T­ FVUN<V«i>¯-O*‰*†° JY;A<V„UœQt;UœQ2<:&C‡B@(;¯NF2>lg”QSR;„ @yBU8kR;CBœQSR›:U8;E­ „>lUDWAQtGlBDUœQNQSBD;nUbW¯S>F2giCEQVU‚>&WrUN<vC4:&CUB8C+yB;_Qt>iCA<<;A<z<-QSR; m‹h| >¯*O*‰_†1QS> ­~>FV«G PF;+„F2;A<;+WAQtUDW {1QSR;›gi;CW1„F2>„>FpQSUD>W0>¯PO*‰*†˜CEQNQ FVUy @QtCEyB8;YQp> ­Y> FV«˜Cgr>&W{ ­Y>&FV«UDW`{ <Œ@y “;kEQ2<z°P}tW€> @F1<ŒQN@(dAeTGCEy> @Qr–¦À >¯rkCA<;A<1>¯rO*‰_†ŸUDW£­Y>&Ft«UbW`{ˆ­Y>lgr;W€k4>T@(BDd£y(; CEQ8QSFVUy @Qt;d QS>Á­~> FV«°~‰IRT; <ŒQtCQSUN<ŒQSU8kCB „> ­Y;+F¸­YCA<™UDWl<S@h¯t¯VU8k‡U8;WAQ0QS> „Ft>T:TUDd; C kBD;4C+F™k>WkB@<2UD>hW F2;+{CF2d&UDW`{ QSRUN<™¯NF2C4kEQVU‚>&W UDW”­r>FV«UDW { gi;Wh°Xr> ­r;z:;+F2G U’QK<2RT>T@(BDdÁy;€y>FVW; UDW giUbWd QSRCzQ´QSR; kCBDkE@(B8CEQtUD>&WY>l¯-m‹h|]UDW :>lB:&;d#­r>FV«rUDW\{;W;+F2CBDGC‡WTd ;A<SQSUDg CzQt;A<6>l¯•m‹h|K­Y;+F2;RUD{lRT;+FUDWr>kkE@„CzQSUD>lW {F2> @„h<w­\UœQSRi{F2;CEQt;FP;EoT„>7<S@F2;Qt>´<2;grUD^ŒF2> @QSUDW;n>&F6F2>A@QSUDW;#giCWA@7CBl­Y>&FV«°T‰IR@<2GhO*‰*†1kCA<“;A<·k> @Bd y;k>&Wh<2U8d;+F;d™CA<rCzQNQSFVUy @QtCEyB8; Qt>¸­Y> FV«™¯S>FrCEy> @ QqQNR`F2;;^V?A@(CFŒQt;+F<Y>&¯ngrCB8;yB@(;^tk>lBDB8C+F#­Y>&FV«;F<2G QN­~>^ QSR`UF2dh<q>l¯P¯t;‡giCB8;›yBœ@7;^Vk>BDBCF_­Y>&FV«;F<qC+Wd˜gr>F2;#QSRCW0RCB¯·>l¯P¯t;‡giCB8; BD> ­r;+F*{F2C4d; <2;F:U8k; <G <2CB8;A<·C‡WTd kB8;+F2U8kCB7­YRUœQt;^Vk>BbB8C+Fw­Y>&FV«;F<z°A|q<ŒQSUDgiCEQt;n> ¯m‹h|ƒUDW›­Y>&FV«UDW { ­Y>&gi;W UDWM>T@F*<ŒQN@(d e\­iC < kBD>h<2; Qt>™QSRCEQik4C+BDkE@(B8CEQt;d€UDWˆQSR;˜H]>WAQSF2;CB\<SQN@(dAeŸža¢¢À¡1k>g\„C+F2UDW {ˆQSRT;KUDWk‡U8d;Wk;Z>l¯ <Œ@Ft{lU8kCB F2;BD;C <;€>&¯ QSRT;€g ;dU8C‡W”WT;+FŒ:(;ˆy;zQN­r;;W”g CW@(C‡BiCWd”W>W^VgiCWA@(CB\­r>FV«;+F“<ÃUbW —— –^a¢°DL @F ;A<SQSUbgiCEQt;<I­Y;+F2;CBN<2>ikBD>7<“;_Qt>#QSRT>7<;>&¯hQSR;UDF*<ŒQN@(dAe\­rRT;WY­Y;>WBbeMk>Wl<2U8d;+F2;d\yB@(;^Vk>lBDB8C+F-­Y>&Ft«;+F< (. HAL author manuscript. . . . .  . inserm-00256944, version 1. . . (. . ). .

(43) HAL author manuscript. >¯Iy&>TQSR1{;+WTd;+F< °h‰wR;›B8CEQ8Qt;+FPF2;<Œ@(BœQ2<<Œ@{{;A<SQwQSRCEQ6­~> FV«^ŒF;+BDCEQt;d1¯tCkEQt> F<*UDWkF2;CA<2;#QSR;\F2U<t«˜>l¯vO*‰_†G y @Q]gY>&F2;ŠF2;+¯SUbW;4d gi;EQSRT>ld>BD>{&e <2R> @(BDdĄF2> :UDd; gr>F2;Á„F;k+U<“; C<<2; <“<2g ;WQƒ>&¯KQSRT; ¯SC4kEQt>&F“< UDW :>lB:(;dh°m‹h| d&UDd1W> Q-QtC«;#UWAQt>0Ckk4>T@WQvC+W eMUbWdU:hU8dA@(CB•kRC+F2C4kEQt;+F2U<ŒQtUDk <*>¯-­Y>&FV«0CWd W>W^N­r>FV« ;EoT„>7<S@F2;r>&F*gr;dU8kCBwRUN<ŒQt>FŒe0CWd QSRA@<qdU8d´W> Q·d; Qt;zF2g›UDW;#QSR;rkCz@<2CB-F2;B8CEQtUD>Wl<2RUD„´y;zQN­r;;W0O*‰*† C+WTd~­Y>FV«iC QQSR;UDWdU‚:(U8dA@(CBlB8;+:(;BN°DL. inserm-00256944, version 1. n! 

(44) %)“. |v„UDdl;grUD>lB‚>&{U8kACB*<Œ@FV:;U8BB8CWk;0>&¯xO*‰_†KUDW C {;‡WT;+F2CB6„>&„ @(BDCEQtUD>WKUDW˜QSRUp<r<SQN@(dTe™<2RT>T­Y;dÃC1RUb{R;F UDWkUd;WTkA;Z>&¯iO*‰*†šUDW™QSR; ­Y>&FV«UDW`{š„>„ @B8CEQSUD>WŸk>gr„C+F2;d£Qt>™QSR;¸WT>&WT^p­Y>&FV«UDW {€„>„ @(BDCEQtUD>&W(°_m <Œ@y<SQtC+WAQtUDCB„F2>„>&FNQSUD>W1>¯PkC <;A<q>l¯6O*‰_†0dU8C+{lWT>7<;d1UbW QSRT;›BD> ­Y;+FP{F2Cd;#­rRU’Qt;^Vk>BDBCF·­Y>FV«;+F*C+Wd yB@(;^Vk>BbB8C+F]­r>FV«;+FƒkCQt;+{> FVUD; <ˆ­Y;+F2;CEQQSFVU’y @QtC+yB8; QS>Ä­~>&Ft«h°1m#B’QSR> @{R QSR;ŠF2;A<Œ@(BœQ2<Ÿg#@<SQ™y; k>W¯ŒU Fagi;dKUDW >TQSRT;+F\CF2;CA<G"QSRT;4e „F2>T:U8d;´U8gr„>&FNQtC+WAQqWT;E­ UDWh<2UD{RAQ2<QS>Kgr;4CT<S@F2; QSR;´UDgr„CkEQx>&¯xCAW ;Eo&kA;<<wF2UN<V«i>¯-O*‰*† UDW#QSR;_­Y> FV«UDW {r„>„ @hB‚CEQVU‚>&WrCWd#Qt>‘QtC+FV{;Q•„ F2;z:;WAQtU:;CkEQSU‚>&W(°  !‘¨YŠ³. \3 ~', ‰wR; CE@QSRT>&F“<ˆQSRCW « J\F<]cwU8;+FVF; uv>&WTkRCgr„ QtG mnWW;Š \U8;‡U8BB8C+FŒQƒCWd zCk?A@7;A< ~B8;‡UDW ¯S>FˆQSRT;‡UDF „C+FŒQSU‚k‡UD„CEQtUD>W UDW€QSR;Ÿ†;‡WQSUDW;‡Bqj1;EQN­Y> FV« C+Wd€J\F1cU8;+FVF2;K=*@(kC+e”¯S>F´RUN<R;BD„”UbWŸ„F2;„C+F2UbW{ŸQSR; giCWA@•<2k+F2U„ Q“° . 

(45)   ~!,. ° m F2g U’QtC+{;´cwGP¹x;+FVFVeƒf#GPH]CEQNQSRT;E­i<Vj0† °q† QtCEQSU<ŒQtUDkCBngr;EQSRT>ldl<iUDW€gi;d&U8kCBqF2; <2;C+Fk‡R(° o¯S>F2dG ¹xBDCk+« ­r;B8B c @yBUN<2RT;+F<2G§§Žh° ° mQSF2>h<VRU6}2GPf@(g›gi;A<z<>&WZO*G  >&R`Wh<<2>W˜=xGP;EQnCBN° c•F2;E:&C‡B8;Wk;0>&¯xkC+FV„CBQN@W`W;B<VeWd F2>gr;´UDW]C {;+WT;+F2CB„>&„ @B8CEQSUD>Wh° zmH]mº———7¬’h¥•®N¢`Ž^+¢¥° ).

(46) Žh° ¹xBDCWdaJncwGl=*@(d>lBD¯S;+F† H °lO*BUDWUk4C‡B6<Œ@FŒ:(;UDBB8CWk;\>¯PkCFV„CBlQN@WW;B<VeTWd F2>gr;\UbW QN­Y>0C+F2;CA<·>&¯ QSRT;_\WUœQt;4d ~UDW{d>lgrGw——-^Œ§§-°wj ;z@Ft>&Bji;E@F2>h<Œ@FV{\c6<Œe&kRUCzQSFŒe\§§Žh¬ ¦ –•®p¤¦ –^+¤¦—h° –° JYCE:U8; <uvG ;BB8g CWrXrGlc@WW;EQNQwuq°(†T@FS:;UDBB8CWk;\>¯I­Y>&Ft«^ŒF2;BDCEQt;d1kCFV„CBlQN@WW;Bw<VeWd F2>gr;\UW H£CA<z<2CkR@<“;EQQ2<G#—— ^+——¦®wC F;+„>&FNQ¯NF>&g QSRT; H]C <“<2CkRA@•<2;zQNQ2< †;+WQSUDW;‡B6|:(;WAQ·j >AQSUD¯SU8kACzQVUD>W †el<SQt;gÁ¯S>F k4kE@„CEQSUD>WCB=UN<V«iž† |"j´† =¡ °Amng P}VWTd~H£;d\§§-¬ Ž—®‚¢¥`^V¦-° ¢°  C4yB8;k«lUO ~GlmnWdC+FVe\H]‰6G&‹•BD>;EQt;+FwH ~Gh;EQIC+BN°Ac•F2C4kEQNU8k;„C+F2Cgi;EQt;+F®A|vBD;kEQSF>ld UDC{lWT>7<SQSUDk›<ŒQN@(d U8; < UDWkC+FV„CB›QN@WWT;B´<VeWd F>&gi; °=;„>&FNQ>&¯1QSR;€mngi;‡F2UDk4C‡WŠm\<z<2>kUDCEQtUD>WŠ>&¯1|*B8;kEQSFt>ld U8C+{W>h<ŒQSU8k H£;d&U8kUDW;Gˆmngi;+F2Uk4C‡W mnkCd;g›e >l¯]j ;E@F>lBD>{&e CWd mng ;FaU‚kACW mnkCd;g›e >¯ c"R eh<2U8kCB H£;d&U8kUDW;C+Wd#=x;RC+yUbB8UœQtCEQtUD>Wh°j ;E@F>&BD>{e\§§ •®¢¥(®p¢¥`—^+¢`— ° ¤h° ~B8;‡UDW y(CE@(g JYf#G\† @(BbB8U:(C‡W H]G_¹xC+FV«;+F~jYJM°Pm „>k+«;Qr{ @UDd; Qt>ƒ;+„UDd;‡grUD>BD>&{e°†„F2UDW {;+FG ji;E­”9~>FV«G§§¦l° ¦h° H£k¸‹•C+F2B8C‡WT;Kf 4°P}2d;WAQSUD¯VU8kCEQtUD>WŸCWdˆ„F;4:&;WAQtUD>&Wƒ>l¯\­Y>&FV«^NF2;+B8CEQt;4d€kC+FV„CBQN@WWT;‡B\<VeTWd F2>lgr;`° uvCWk4;EQ•§§-¬Žl¢`¦®Nz–¤^+z–¦h° ¥° H£>&WTd;‡BDB8UYH£Grf#U8C‡W`WUDWlUr‹•Grf#UDCkkRU\HŸ°nO*C+FV„CB#QN@WWT;B <VeTWd F2>lgr;€UDWkU8d;Wk;€UDW”Cˆ{;W;F2CAB „>„ @BDCEQtUD>Wh°j ;E@F>&BD>{e\§§ h¬D¢¥(®±h¥`—^S— –° —h° jiCEQSUD>WCB =x; <2;C+Fk‡R O*>T@WTkUBN°Ÿ‰RT; jiCEQtUD>&WTCB”m\kCd;g\e >¯ †k‡U‚;‡WTk;A<z°ˆHZ@<2kE@(BD> <t«;‡B8;EQtCB JrU8<2>F2d;+F<qC+WTdMQSRT; >&Ft«„BDCk;®&uv> ­ yCk«˜C+WTdM~„„(;+FP|o`QNF2;grUœQSe0gY@<kE@(BD> <V«;B8;EQtCB•d&UN<>&F2d;F<z° jiCEQSUD>WCBhmnkC4d;‡gre\c•F2;A<“<2G CA<2RUDW{ Qt>&WnJrO*G§§-° §h° ji>&Fdl<pQSFt>g JnuvG_Jr; † Qt;¯SCW>ˆ‹•G \U8;+Ft«C+WAQ\=xmnG_uvC+e(d; cHŸ°P}VWTkUd;WTk;™>&¯Yd&U8C+{W>h<2;dƒkC+FV„CB QN@W`W;B <VeTWd F2>g ;UDWrC{;+W;+FC‡B„>„ @(BDCEQtUD>&W(°‡|v„UDd;g U >&B‚>&{e˜——l¥¬ —®’Ž –^VŽ –h¢° ° c@WW;zQNQ¸uvG ;+{lgYC‡WŠJ#XM° >&FV«^SF2;+BDCEQt;4d g#@•<2kE@(BN>h<V«;BD;zQtC‡B0dUN<2>F2d;+F<E®YQSR;”;„lUDd;giUD>lBD>{lU8k ;E:U8d;Wk;C+WTd#QSR;d;+yCEQt;`° w|PB‚;AkzQSFV>g\e>{F ~UbW; <2UD>BN° §§ –h¬Sz–•®pŽ^ŒŽh° z° =x;g\„(;‡BJYGT|6:CW>¯Œ¯¹Gm#giCdUD>Yc"O*G;EQ"C‡B ° O*>Wh<2;Wl<V@<6kFaU’Qt;+F2UDC‘¯S>F-QSR;kB8C <<2U8¯VU8kCEQtUD>&WY>l¯•kC+FV„CB QN@W`W;B <VeTWd F2>g ;UDWr;+„U8d;‡giUD>lBD>{UDkC‡B<ŒQN@(d U‚;T< °Amng c@yBU8k_Xr;4C‡B’QVR˜——l¥¬D¥¥(®Nz––¦^+z–h¢° . HAL author manuscript. ). ). inserm-00256944, version 1. . . . .

(47) . HAL author manuscript. =x>?A@(;+B8CE@F2; 9\G XrC O*G c";+BDU8;+F2^tO_C4dTe H£O‘° =n A<;CE@ ;+o„ +F2UDgi;‡WQtCB d; <Œ@FŒ:&;UBB8CWk; +„UDd g U‚>lBD>{lU8?A@(;¿d; < QSFt> @yBD; < gY@<“kz@hBD>^a<?A@(;‡B8;EQNQSU‚?A@(;A< dCWl< B8; < c"C+eh< d;¿B8C uv>UF2;`° † @FŒ:&;‡UDB8BCWk;n;W „>„ @hB‚CEQVU‚>&Wr{ W +F2CB8;#dA@Ã<VeTWd F2>g ;~dA@0kCWCB•kC+Ft„lUD;WMdC‡Wh<vB8;‘H]CUDW;\;EQ•uv>lUF2; ;+WZ§§ °-}VW<ŒQtUœQN@Qnd; :;UB8B8;¸<2CWUœQtCUF“;G§§ –°  

(48)          "!$#&% '   )($ +*,,-. /0 +12354. 6"  7' 98. inserm-00256944, version 1. z–° =x>h<<2U{W>lB H£G † Qp>lk+«0†G cwCQNFSe\uvG&mF2g1<ŒQSF>&W`{Y¹~°`O*C+FV„CB QN@WW;B<VeWd F2>lgY;®‡­rRTCEQwU<ICEQNQSFVUy @QtCEyB8; Qp>~­~>FV« q‰IRT;_H]>WAQSF2;CB†TQN@(dAe(° k4kE@„\|PW :UF>&W#Hƒ;d˜——¦l¬D¢–•®‚¢—^a¢Žh° ¢° † Qt;E:&;+Wh<  O_G† @W€†G¹x;C+F2d™OH£G_;QnCBN°6O_CFV„CBQN@WW;B<VeWd F2>gr;˜UbWÃ=x>lk+RT; <ŒQt;+F2GH UbWWT; <2> QtC+G —¤-Qp>¸—l¥`§°+ji;E@Ft>&BD>{e˜—l¥¥¬ Žl¥(®pŽ –^z–h¥° ;:. ).

(49) '_µh%8 Jr;A<k+F2U„ QtUD>&WY>&¯hQSR;UDWkU8d;WAQ"kCA<;A<6>¯-O*‰*†•®‡|PB8;kzQSFV>d UDC+{W>h<ŒQtUDk¯ŒUDWdUbW{h< 

(50)        . !" $#%&(' ) *,+-.. HAL author manuscript inserm-00256944, version 1. &/ 013245 6  7 98: ) <;3%2:=>?7 #A@ CB D2:,+

(51) . E 7FG 84 6>H

(52) 6?#6 1 08I ) 0;J2:47 #JK (2ML,+ . NO?LPH*Q> 6 13 7 98:G )) 7 R7 >,@ PB D2S,+ Q. NO EGT?U VKÃ 4W3XY+ . UZ 6 241 05A ) [;%   H 02:79 ]\3  7 4 ) <;% Z >H^

(53) 0 _\6 1 Z 7#`2?H^" >a+ Q. +

(54) ._9Q4+ . +

(55) ._9Q4+ . + ._9Q4+ . . '. h. `b c%d"edfd"g6d7hjidRk6ilnmpoqsr"tvu1w>xay<zk"{l7|"epy]|

(56) oqql y<}6o~61hj~>€,eo%>‚GƒAd

(57) ~1„GƒA|

(58) dyl y]o7m! _†‡d

(59) mmpl |Fe$h~6€,eˆ6l‰qh€ˆ9eQdŠ~GJil"me‹,qphy[eyt ql y[}Gl

(60) |"ehg6l

(61) ijŒ7c%d

(62) ed`d

(63) qll

(64) Ž9}1ql yy0l

(65) d5yCeˆGl}Gl

(66) q|

(67) lŠ~ed

(68) €1l`o7mPh=~6|

(69) h>lR~9e|

(70) dyl yF6‡1l

(71) lne=ˆ6l_el

(72) Že6mpoq]1l"ed

(73) hiy]o ~JeˆGl!c,‘’|"qh*el"qhjd. '*µh%8?“!&}tWkUDd;‡WTk;>¯-O*‰*† C4kk>F2d UDW {\QS>iC+{;G {;+WTd;+F6C+Wdr;g\„BD>&egi;WAQ6<ŒQtCQN@<7” U  +<8 R". £ £ £ £ ¤f > '. •—–]˜?™Gš ™˜Mœ>–‰ž]™Ÿ  !šn™˜Mœ>–‰ž]™Ÿ +.¢¡0Q >7 1 +.¢¡0 17 > + 1. PB + 6. PB + 6. 1B h + . 1B + h

(74) . 1B + 6. PB + . PB + 6. 1B + 1. 1B + Q. PB '. . . ' '. . N›™Gš ™˜Mœ>–‰ž]™Ÿ  !šn™˜Mœ>–‰ž]™Ÿ +.¢¡0Q >7 1 +.¢¡0 17 > + . PB + 6. PB + 6. PB + 6. PB +  . PB + . PB + . PB + 6. PB + 6. PB h + 6. PB . . '. . ¥  ) 72I6V9 ¦2I>5§;9#*¨ Q24\^" © ;3©ª>H^ 61 "›1 › 1*H^«4›&/7 ¬ Š\ Š79 6 H2 Z  f[+ .‰9?2: >4 73 1%  J )­ ¤ E \7 *

(75) ® J\3 ""6£<871 "B.

(76) '*µh%!~+%8 2‚¶(NP 0 V2µ)h2µh%z +

(77) +28 v w!n'x,M

(78) 

(79)  \2r

(80) 

(81) )$ 2`.

(82)  2  .M 0 T$ z4´$ • HAL author manuscript inserm-00256944, version 1. – 3 _œ

(83) –Pš 

(84) 6™‰–!ž, • –!˜?™Gš >B  02: " ]B ­  ) ' &/62:7®F1( &?62:7I9?2419 " CB!  ) 

(85) "61 ]B¤f7 7; >=9

(86) ®6

(87) "6  ,\  ) 

(88) "6>$ CB*+ &M7 _ >, &D; £ => &/6 -7 R CB*.,*H1£< >=> &/6/ -3 " CB T >£ &?G0 -?\7 R"Q2 1 N G™ š >B  02: " ]B ­  ) 2:7® E >"2:7®247 R CB!  ) 

(89) "61 ]B¤f7 7; >=9

(90) ®6

(91) "6  ,\  ) 

(92) "6>$ CB4+ &M Q 1 &/; 1£< 11 &/6' -7 R CB*.,*H1£< >=> &/6/ -3 " CB T >£ &?G0 -?\7 R"Q2 1. !a+- .. T +- ..  ­ ¡. U! ©+-." ­ ¡ #. 1B !B !B !B PB !B !B. M+ !B . 4+1B . 4+ !B 1. 4+ PB 6. 4+ !B 6. :+ PB 1. 4+ PB 6.. 1B $ 3B G£ !B % PB ) 3B £1B  PB ) 3B £1B  PB ) 3B £ PB * !B ) PB £ PB % PB ) PB £ PB %. £. !B PB PB PB PB PB PB. :+ !B . :+ !B . 4+ PB 6. 4+ B . M+ PB 6. 4+ PB 6. 4+ PB 6.. 1B ) 3B G£ !B % PB 3 3B £1B % PB ) 3B £1B % PB ) 3B £ PB * 1B ) 3B G£ !B" !B $ 3B £ PB %.  . . . . . '. . . '. . . . . £. . . £ £ PB ) 3B%£ PB % PB ) PB 4£ B % £ . . £. . .  . . £ £ £ £ PB $ hB 4£ PB  £.  _7 R"Q5&M6 -* >H $ 0;§8 > 4 ) 0; Š7« ]¢+-V."6\^7  >71 >¢ ) ;3¢  7H\ 6 › ;P ¢ 77 >P\P>\H 6V ) 0;/N©>1£0R £+` D1 7« T +-.266H32 Z 7 ,S\^7  >79 04 ),­ ¤ E j >71 ` GŠ57« ­ ¡ %76 - Q ) 7 >%1  #1<« ” J )  "7 1J >H\.

(93) '*µh%P\=x;‡B‚CEQVU:&;FaU8<V«<6C+WdrCEQNQSFtUœy @QtCEyB8;F2UN<V«i¯NF2CkEQtU8>&W<6>&¯•O*‰*† Ck4k> F2d UDW {\Qt>\UDWdA@•<ŒQSFŒerUDW ;EoT„>7<;d\„;+F<2>Wl< HAL author manuscript inserm-00256944, version 1. ¡ šnŸ‰ 

(94) %!ž + T?UM­ V  .Š •—–]˜M™6š 1B U  = 7HP <H  !B ­ 1 0 H

(95) 6 PB>N›6H ) 1

(96) [H *6 !B E  0# 1%$>H^  5 PB T >£ &M6 -$M\3 ""6 1 N›™Gš 1B U  = 7HP <H  !B ­ 1 0 H

(97) 6 PB>N›6H ) 1

(98) [H *6 !B E  0# 1%$>H^  5 PB T >£ &M6' -?\^7 RF6"1. !a+- .. T +-..    ­ ¡  . U! ©+- ." ­ ¡  #. !B PB A1B PB !B. h%+ B 6.. !B ) ^B £ CB % !B )V5B £ PB % !B!VB £ !B % 1B )VB £ !B". PB $ 3B £ h1B  £ !B! 3B £ !B % PB ) 3B £ PB" £. 1B $ 3B £ !B % PB ) PB £ !B % !B )VB £ !B % PB ) 3B £ PB *. £ PB ) PB £ B  CB $ ^B 4£ PB  £ £. :+ PB 6. %+ PB 6. :+ !B 6. 4+ PB 6. . . . . '. . . . . h%+ PB 6. M+ B

(99) .. B B !B 1B PB. . :+ !B 6. M+ PB 6. 4+PB 6. '. . . . . . . . . . . . % _7 R"6 &(6 '-:>H j( <;3%83 >  ) [;%9

(100) 7«]a+-."69\P  171 3a ) <;*>H^ 0 84( [;J77 1 \>\H7 64 ) <;JN©1*1£0R £+f %1  « T +-."69GH32 Z 7 D\^7  >71 J )­ ¤ E j 79 _ 6

(101) 7« ­ ¡6 - Q ) 7 11  0#1<« ” % ) 7 "7Q >JQ >H\V« ª \P  ) 4Š

Références

Documents relatifs

To test whether the vesicular pool of Atat1 promotes the acetyl- ation of -tubulin in MTs, we isolated subcellular fractions from newborn mouse cortices and then assessed

Néanmoins, la dualité des acides (Lewis et Bronsted) est un système dispendieux, dont le recyclage est une opération complexe et par conséquent difficilement applicable à

Cette mutation familiale du gène MME est une substitution d’une base guanine par une base adenine sur le chromosome 3q25.2, ce qui induit un remplacement d’un acide aminé cystéine

En ouvrant cette page avec Netscape composer, vous verrez que le cadre prévu pour accueillir le panoramique a une taille déterminée, choisie par les concepteurs des hyperpaysages

Chaque séance durera deux heures, mais dans la seconde, seule la première heure sera consacrée à l'expérimentation décrite ici ; durant la seconde, les élèves travailleront sur

A time-varying respiratory elastance model is developed with a negative elastic component (E demand ), to describe the driving pressure generated during a patient initiated

The aim of this study was to assess, in three experimental fields representative of the various topoclimatological zones of Luxembourg, the impact of timing of fungicide

Attention to a relation ontology [...] refocuses security discourses to better reflect and appreciate three forms of interconnection that are not sufficiently attended to