• Aucun résultat trouvé

CONDUISANT A LA TEM

A. LES ACTIVATEURS DE LA TEM !

II. PROCESSUS CELLULAIRE

CONDUISANT A LA TEM

A.LES ACTIVATEURS DE LA TEM

!

L>!G%.)'!P=;=&>G'!+'.!(>;+%+>).!%C4G%V*=.!+>;.!G>!&=P*G>)%1;!+'!G>!FAI!'.)!)&-.!G1;P*'/! +%<'&.! .)%C*G%.! (1CC'! G'! F8_Ka9! G'! _8_9! GYA8_9! GYH8_9! GYD8_9! G'! 0$8_9! G'.! 1'.)&1P-;'.9! t;)9! N,,9! G'.! (S)1]%;'.! %;2G>CC>)1%&'.9! GY,S41B%'9! G'.! 1;(1P-;'.! 7>.E\"9! A&O5"9! 4R#! C*)='! ')(! TF,%'&S!')!>G@9!"ffbU@!L'.!>()%<>)'*&.!+'!G>!FAI!(1CC'!G'!F8_Ka9!G'!F^_K`!')!GYD8_!4&1+*%).! 4>&! G'.! ('GG*G'.! .)&1C>G'.! 1*! 4>&! G'.! ('GG*G'.! )*C1&>G'.! %;+*%.';)! GY>()%<>)%1;! +'! 2>()'*&.! )&>;.(&%4)%1;;'G.! +'! G>! FAI! TF,%'&S! >;+! NG''C>;9! "ffcU! (1C4&';;';)! G'.! C'CO&'.! +'! G>! 2>C%GG'!!ODLD!TO>.%(!,'G%4KG114K,'G%B!2>C%GSU9!8N3!T811.'(1%+U9!p_D!Tl%;PK2%;P'&!AKO1B!O%;+%;P! ,1C'1O1BU! T0'%;>+1! ')! >G@9! "ffdU@! J*! (1*&.! +'! ('))'! ),-.'9! 4>&C%.! +%<'&.! >()%<>)'*&.! +'! G>! FAI9! ;1*.! >GG1;.! ;1*.! %;)=&'..'&! 4G*.! 4>&)%(*G%-&'C';)! >*! ! &ZG'! +*! F8_Ka! ! ')! +*! F^_K`! T2>()'*&! G%=! X! GY%;2G>CC>)%1;U! +>;.! GY%;+*()%1;! +'! G>! FAI@! A;! '22')9! +>;.! ;1)&'! 4&1[')9! ;1*.! ><1;.! *)%G%.=! G>! G%P;='! +'! (>;('&! 4*GC1;>%&'! JRQb! +1;)! GY'B41.%)%1;! >*B! (S)1]%;'.! F^_K`! ')! F8_Ka!!4'&C')!GY%;+*()%1;!+'!G>!FAI!+'!C>;%-&'!&=<'&.%OG'@!

)

TGF- β

L>! 2>C%GG'! F8_Ka! (1C4&';+! )&1%.! %.121&C'.! +'! F8_K! a! TF8_KaK\9! K"9! K#U9!')! +W>*)&'.! (S)1]%;'.! %C4G%V*='.! +>;.! G>! +%22=&';(%>)%1;! ')! G>! 4&1G%2=&>)%1;! ('GG*G>%&'! (1CC'! G'.! 5I0! TO1;'! C1&4,1P';')%(! 4&1)'%;.U9! G'.! %;,%O%;'.! ')! G'.! >()%<%;'.@! Ti*! ')! >G@9! "ffbU@! L'.! )&1%.! %.121&C'.! +*! F8_Ka! .1;)! (1+='.! 4>&! +'.! P-;'.! +%.)%;().9! V*%! (1;.'&<';)! )1*)'21%.! df! +Y,1C1G1P%'!';)&'!'*B!TI>..>P*=9!\bbeUT$'&S;(]!')!>G@9!"ff\UT3,%;!')!>G@9!"ffQUTI>..>P*=9! "ffeU@!L'.!&=('4)'*&.!+*!F8_K!a!!.1;)!(1C41.=.!+'!+%22=&';)'.!.1*.K*;%)=.@!3,'l!GW,1CC'!%G!

! Qd! 'B%.)'!.'4)!.1*.!*;%)=.!+'!)S4'!H!')!(%;V!.1*.!*;%)=.!+'!)S4'!HH@!L'!F8_Ka!.'!G%'!'B(G*.%<'C';)! X!*;!&=('4)'*&!)=)&>C=&%V*'!(1C41.=!+'!G>!.1*.K*;%)=!+'!)S4'!H!F8_Kƒ7\!TJLgR!')!Fa7HU!')! +'!G>!.1*.K*;%)=!+'!)S4'!HH!F8_Ka7"!TI>..>P*=9!"f\"U@!

L'!F8_Ka!>!+'.!'22').!%;,%O%)'*&.!')!.)%C*G>;)!.*&!G>!4&1G%2=&>)%1;!+'.!('GG*G'.9!>P%..>;)! (1CC'! .*44&'..'*&! +'! )*C'*&! ')! 1;(1P-;'@! $>;.! G'! +=<'G144'C';)9! G'! F8_Ka! 2><1&%.'! G>! +%22=&';(%>)%1;! +'.! ('GG*G'.! ')! %;,%O'! G>! 4&1G%2=&>)%1;!w! >G1&.! V*'! +*&>;)! G>! )*C1&%P=;-.'! G'! F8_Ka! .=(&=)=! 4>&! G'.! ('GG*G'.! )*C1&>G'.! 4'&+! .1*<';)! .>! 21;()%1;! %;,%O%)&%('! ';! 2><'*&! +'! .1;! >()%<%)=! 1;(1P=;%V*'! TN%'P'G! >;+! I>..>P*=9! "ff#UTF,%'&S9! "ff"UTN%'P'G! >;+! I>..>P*=9! "ff#UT$*C1;)!>;+!J&)'>P>9!"ff#UTM%;PG%;P!')!>G@9!"ffQU@!

L'! F8_Ka! '.)! *;! 41GS4'4)%+'! &=P*G>)'*&! C*G)%21;()%1;;'G! V*%! (1;)&ZG'! 4G*.%'*&.! >.4'().! +'.! 21;()%1;.! ('GG*G>%&'.9! (1CC'! G>! 4&1G%2=&>)%1;9! G>! +%22=&';)%>)%1;9! G>! C%P&>)%1;9!! GY>414)1.'9! GY>+,=.%1;9! GY>;P%1P';-.'! ')! GY%CC*;1K.*&<'%GG>;('@! L'! F8_Ka! '.)! G>! (G=! +*! &';21&('C';)!+'!GY%CC*;1K.*&<'%GG>;('!')!G'.!('GG*G'.!)*C1&>G'.!V*%!.'(&-)';)!+*!F8_Ka!';! 21&)'! V*>;)%)=! .1;)! 4&1)=P='.! +'! GY%CC*;1K.*&<'%GG>;('@! L'! F8_Ka! '.)! G>! 4&'C%-&'! <1%'! +'! .%P;>G%.>)%1;!+=(&%)'!41*&!%;+*%&'!G>!FAI@!!L>!<1%'!+'!.%P;>G%.>)%1;!+*!F8_Ka!'.)!>()%<='!G1&.! +'!G>!G%>%.1;!+*!F8_Ka!><'(!G'!(1C4G'B'!)=)&>C=&%V*'!C'CO&>;>%&'!(1C41.=!+'.!.1*.K*;%)=.! Fa7HH! ')! Fa7H! TNA7hFD7! 4&1)=%;'! ]%;>.'.U@! L>! .1*.K*;%)=! Fa7HH! >()%<'! 4>&! 4,1.4,1&SG>)%1;! +%&'()'! G>! .1*.K*;%)=! Fa7H@! 3'))'! +'&;%-&'! %;+*%)! G>! 4,1.4,1&SG>)%1;! +'.! 2>()'*&.! +'! )&>;.(&%4)%1;! NC>+"! ')! NC>+#! V*%! .'! (1CO%;';)! ><'(! NC>+Q! 41*&! 21&C'&! *;! (1C4G'B'! )&%C-&%V*'@!3'!+'&;%'&!&=P*G'!GW'B4&'..%1;!+'!P-;'.!(%OG'.9!.*%)'!X!.>!)&>;.G1(>)%1;!;*(G=>%&'@! L>!.%P;>G%.>)%1;!NC>+!&=P*G'!>%;.%!GY'B4&'..%1;!+'!)&1%.!2>()'*&.!+'!)&>;.(&%4)%1;9!N;>%GhNG*P9! p'O\hp'O"9! Fk%.)! V*%! .1;)! %C4G%V*=.! +>;.! G'! 4,=;1C-;'! +'! )&>;.%)%1;K=4,%)=G%1K C=.';(,SC>)'*.'@!

$>;.!G'!(>.!+'!G>!G%P;='!JRQb9!G'!F8_Ka!'.)!(>4>OG'!+Y%;+*%&'!G>!FAI!><'(!G>!4'&)'!+'! GYAK(>+,'&%;'! ')! G>! &=1&P>;%.>)%1;! +'! _K>()%;@! 3'))'! FAI! '.)! >C=G%1&='! 4>&! G>! 4&=.';('! +'.! (S)1]%;'.!HLK\!a9!F^_K`!')!H^_Km@!LYHLK\a!')!G'!F^_K`!.'*G.!.1;)!>*..%!(>4>OG'.!+Y>*PC';)'&!G>! FAI!%;+*%)'!><'(!G'!F8_Ka@!L>!(1CO%;>%.1;!+*!F8_Ka!><'(!G'!F^_K`!'.)!(>4>OG'!+'!(,>;P'&!G>! C1&4,1G1P%'!+'.!('GG*G'.!>*!O1*)!+'!Qe,!')!+'!21&C'&!+'.!('GG*G'.!2%O&1OG>.)%V*'.@!01*&)>;)9! G'!)&>%)'C';)!.'*G!><'(!G'!F8_Ka!CuC'!>*!O1*)!+'!\"![1*&.!;Y'.)!4>.!(>4>OG'!+Y><1%&!*;!)'G! '22')! TL%*9! "ffeU@! L>! FAI! %;+*%)'! 4>&! G'! F8_Ka! '.)! >*..%! >C=G%1&='! 4>&! G>! 4&=.';('! +'!

! Qe! 7Jt"cQ@d!V*%!.'(&-)'!!G'!F^_K`!')!('))'!FAI!'.)!OG1V*='!G1&.!+*!)&>%)'C';)!><'(!GY%;,%O%)'*&! .=G'()%2! +'! ^_Kr59! +',S+1BS! C'),SG! '41BSV*%;1C%(%;! Tg>k>)>! ')! >G@9! "f\"U@! LY%;,%O%)%1;! +'! NC>+"!OG1V*'!>*..%!G>!FAI!%;+*%)'!4>&!G'!F8_Ka!w!('!V*%!C1;)&'!V*'!('))'!FAI!.'!&=>G%.'!4>&! *;'!<1%'!+=4';+>;)'!+'.!NC>+.!Tg>.>%!')!>G@9!"ffRU@! L'!F8_K!"!"#$%&'()!*&+&,#'-&.'%/$&.'-&'.$),!*$.!#$/,'0+!-K!"#$%&"#'"(&)*!+%,!-.$&)* +>;.!G>!FAI9!(1CC'!4>&!'B'C4G'!G'.!4')%)'.!4&1)=%;'.!8F0>.'.!T7,19!7>(!')!(+(Q"U9!G>!<1%'! +'.! IJ0g%;>.'.TC%)1P';K>()%<>)'+! 4&1)'%;! ]%;>.'U! ! ><'(! ;1)>CC';)! G'.! (K[*;K^! )'&C%;>G! ]%!"#$#%& '()'$#& *$)+& ,-./,0)1$#& *"!#& /"& 21(23"!,#"',(!& *)& 45'(#0)$/$''$& *6"4',!$& $'& /"& !"#$%&'&%() '*""+"#&,*-.+) /&*0) "#) 1.&*) 2345678%) 9+&) &0:&/*) "#) ;"<'.;=0*K.S;),>.'! ]%;>.'! #! T8Ng#aU!')!>()%<'!G>!<1%'!t;)@!LY>()%<>)%1;!+'!IJ0g!')!+'!0H#g!(1C4G-)'!')!(1;<'&P'!><'(!G>! .%P;>G%.>)%1;!NIJ$@!3'.!<1%'.!4'*<';)!u)&'!>;)>P1;%.)'.!+'.!<1%'.!+'!.%P;>G%.>)%1;!%;)=P&>;)! G'.! 4&1)=%;'.! NIJ$! +>;.! +W>*)&'.! (1;)'B)'.@TI>..>P*=9! "ffeUTt*! >;+! D%GG9! "ffbUTI1*.)>]>.! >;+! D'G+%;9! "ffbUTD1GC! ')! >G@9! "f\\U@! ^_Kr5! T;*(G'>&! 2>()1&! rKG%P,)! (,>%;K ';,>;('&!12!>()%<>)'+!5!('GG.U9!')!0H#!]%;>.'!h!JgF!4>&)%(%4';)!=P>G'C';)!X!G>!.%P;>G%.>)%1;!+*! F8_Ka@! F1*)'.! ('.! <1%'.! +'! .%P;>G%.>)%1;! .1;)! %;)'&(1;;'()='.@! 0>&! >%GG'*&.9! %G! 'B%.)'! +'.! .%P;>G%.>)%1;.!(&1%.='.!';)&'!G'.!+%22=&';)'.!<1%'.!+*!F8_Ka!')!+Y>*)&'.!<1%'.!+'!.%P;>G%.>)%1;!/! 4>&! 'B'C4G'9! GY>()%<>)%1;! +'.! 4&1)=%;'.! NC>+! 4'*)! =P>G'C';)! >()%<'&! G'! &=('4)'*&! X! GYA8_! TA4%+'&C>G! 8&1k),! _>()1&U! ')! %;+*%&'! G>! FAI! T8*%! ')! >G@9! "f\"U! Tg>;P! ')! >G@9! "f\"U!" !"#$%&'$()* '+* (,%-+,* ./,* +#* ('0$#+'(#1'&$* 2%#3K!"#$%!&%'$( !)( *+,K!" !"#$% &'()!!*#+)% ,% -*% (1;<'&.%1;! 4,=;1)S4%V*'!w! (>&! G>! .*&'B4&'..%1;! +'! NC>+d9! *;'! NC>+! %;,%O%)&%('! +'! NC>+"9! OG1V*'!G>!FAI!Ti*!')!>G@9!"ffbU@!

L'.! 4&1)=%;'.! NC>+! \Ke! .1;)! +'.! '22'()'*&.! +'! G>! <1%'! +'! G>! .%P;>G%.>)%1;! +*! F8_Ka@! NC>+#!'.)!G'!C=+%>)'*&!.4=(%2%V*'!+'!GW>()%1;!+*!F8_Ka9!)>;+%.!V*'!NC>+!\9!"9!R!')!e!.'&<';)! .1*<';)!(1CC'!GY%;)'&C=+%>%&'!41*&!G'.!>()%1;.!+'.!>*)&'.!C'CO&'.!+'!2>C%GG'!F8_Ka@!NC>+! c!>;+!d!.1;)!G'.!NC>+.!%;,%O%)'*&.9!V*%!&=P*G';)!;=P>)%<'C';)!G>!.%P;>G%.>)%1;!F8_Ka!h!5I0@! 0>&! 'B'C4G'9! NC>+d! .'! G%'! ><'(! NI:7_! 41*&! 21&C'&! GY*O%V*%)%;'! G%P>.'! A#! V*%! (%OG'! G'! &=('4)'*&!+*!F8_Ka!')!%;+*%)!.>!+=P&>+>)%1;!Tg><.>]!')!>G@9!"fffU@!L>!G%>%.1;!+'!NC>+d!')!+'! NI:7_! >*! &=('4)'*&! .'! )&>+*%)! =P>G'C';)! 4>&! *;'! %;,%O%)%1;! (1C4=)%)%<'! +'! G%>%.1;! +'! NC>+"h#! X! Fa7H! ! T5%'&%'! >;+! I1.'.9! "ffcU! TH;1*'! >;+! HC>C*&>9! "ffeU@! L'.! NC>+! c! ')! d! %;,%O';)! =P>G'C';)! G>! .%P;>G%.>)%1;! F8_Kah5I0! +>;.! G'! ;1S>*! ';! %;)'&>P%..>;)! ><'(! G'.!

! Qb! &=4&'..'*&.! +'! G>! )&>;.(&%4)%1;9! )'G.! V*'! G'.! ,%.)1;'.! +=.>(=)SG>.'.9! 1*! 4'&)*&O';)! G>! 21&C>)%1;!+*!(1C4G'B'!21;()%1;;'G!NC>+KJ$^!%;+*%)!4>&!G'!F8_KaTL%!')!>G@9!"ffcU@!

$>;.! G'.! ('GG*G'.! =4%),=G%>G'.! G'.! 4&1)=%;'.! NIJ$! >()%<='.! 4>&! G'! F8_Ka! %C4G%V*';)! GY'B4&'..%1;!+'.!2>()'*&.!+'!)&>;.(&%4)%1;!JF_#!TJ()%<>)%;P!F&>;.(&%4)%1;!_>()1&!#U!')!N^JHL9! ')!(114-&';)!><'(!('.!4&1)=%;'.!41*&!&=4&%C'&!GY'B4&'..%1;!+'!H$\!')!+'!3$D\!TP-;'!(1+>;)! A!K(>+,'&%;U@!LA_\!TGY'22'()'*&!+'!<1%'!t^FU!')!NC>+Q!.'!.1;)!&=<=G=.!u)&'!;=('..>%&'.!X!G>! &=P*G>)%1;!41.%)%<'!+'.!C>&V*'*&.!C=.';(,SC>)'*B!(1CC'!G>!E%C';)%;'!')!G>!_%O&1;'()%;'! ')!('G>!%;+=4';+>CC';)!+'!G>!Ou)>K(>)=;%;'@!J%;.%9!LA_\!(1K1((*4'!G'!4&1C1)'*&!3$D\!><'(! G'.! 4&1)=%;'.! NIJ$9! 21*&;%..>;)! *;! C=(>;%.C'! C1G=(*G>%&'! 41*&! G>! (114=&>)%1;! 1O.'&<='! 4';+>;)!G'!FAI!';)&'!G>!<1%'!t^F!')!G'!F8_Ka!T^>k.,>+!')!>G@9!"ffdU@!

$'.! ;%<'>*B! >((&*.! +'! F8_Ka! 1*! +'! .1;! &=('4)'*&! +>;.! G'.! ('GG*G'.! (>;(=&'*.'.9! .Y1O.'&<';)! ! 4>&! *;'! >*PC';)>)%1;! >*)1(&%;'! +'! G>! .%P;>G%.>)%1;! +*! F8_Ka! +>;.! G'! C%(&1';<%&1;;'C';)! )*C1&>G9! ')! 4'&C'))';)! >*B! ('GG*G'.! (>;(=&'*.'.! +W*)%G%.'&! G>! .%P;>G%.>)%1;! F8_Ka! (1CC'! *;'! (G=! 41*&! .*&<%<&'! ')! =(,>44'&! ';! 21&C>;)! +'.! C=)>.)>.'.! TI>..>P*=9! "ffeU9! TH]*.,%C>! >;+! I%S>l1;19! "f\fU@! L'! F8_Ka! [1*'! *;! &ZG'! C>['*&! +>;.! G>! 4&1P&'..%1;!+'.!(>;('&.!';!%;+*%.>;)!G>!FAI!<%>!GW>(V*%.%)%1;!+'!4&14&%=)=.!3N3!TI>;%!')!>G@9! "ffeU! TI1&'G! ')! >G@9! "ffeU! TN(,''G! ')! >G@9! "f\\U@! L'.! ;1*<'>*B! C=(>;%.C'.! +*! (1;)&ZG'! =4%P=;=)%V*'! +'! GW=4%..>P'! >G)'&;>)%29! G'.! C%7.! ! ')! G'.! C1+%2%(>)%1;.! 41.)K)&>+*()%1;;'GG'.! &=P*G';)! =P>G'C';)! G'! FAI! %;+*%)'! 4>&! G'! F8_Ka@! A;! '22')9! G'.! <1%'.! +'! .%P;>G%.>)%1;! %C4G%V*>;)!G'!F8_Ka!>()%<';)!+%&'()'C';)!GW'B4&'..%1;!+'!2>()'*&.!+'!)&>;.(&%4)%1;!%C4G%V*=.! +>;.!G>!FAI9!)'G.!V*'!N;>%G9!NG*P9!pA5\9!pA5"9!')!Fk%.)!T0'%;>+1!')!>G@9!"ffdUTI1*.)>]>.!>;+! D'G+%;9!"f\"U@!

! Rf!

(;<=>?!W!A!5'/!;GJ=;D?!FE>!5)(P!XK!

L'! F8_Ka! %;+*%)! G>! FAI! 4>&! G>! <1%'! NC>+! +'4';+>;)'! ')! %;+'4';+>;)'@! L>! .%P;>G%.>)%1;! F8_K! a! 4,1.4,1&SG'! ')! >()%<'! NC>+"! ')! NC>+#! V*%! 21&C';)! *;! (1C4G'B'! ><'(! NC>+Q! ')! &=P*G';)! GW'B4&'..%1;! +'.! 2>C%GG'.!N;>%Gh!NG*P9!pA5\h"!')!Fk%.)@!p'O\!X!.1;!)1*&!+%C%;*'!GY'B4&'..%1;!+'!C%&K"ff@!F8_K!a!>()%<'!=P>G'C';)! +W>*)&'.!<1%'.!+'!.%P;>G%.>)%1;!V*%!;Y%;(G*)!4>.!G'.!NC>+.9!(1CC'!0H#gKJ])KCF67Tg>).*;1!')!>G@9!"f\#U@!

L'.! +%<'&.! C%7! [1*';)! *;! &ZG'! %C41&)>;)! +>;.! G'! 4&1P&>CC'! %;+*%.>;)! G>! FAI@! 0>&! 'B'C4G'! GY'B4&'..%1;! +'! C%7K"ff! '.)! >()%<='! 4>&! G'! F8_Ka@! I%7K"ff! ! OG1V*'! p'O\hp'O"@! L'! F8_Ka! %;+*%)! GY'B4&'..%1;! +'! C%7K\RR! <%>! NC>+Q@! J! ;1)'&! V*'! G>! +%C%;*)%1;! +'! C%7K\RR! %;,%O'! G>! FAI! %;+*%)'! 4>&! G'! F8_Ka! Tg1;P! ')! >G@9! "ffeU@! J%;.%! C%7K#f"9! C%7K#d"! ')! C%7K"fQ! &=4&%C';)! GY'B4&'..%1;! +'! Fa7HH! ')! %;,%O'! G>! FAI! TN*O&>C>;S>C! ')! >G@9! "f\\U! Tt>;P! ')! >G@9! "f\fU@! LY'B4&'..%1;! +'! C%7K"#>! '.)! &=P*G='! 4>&! G'! F8_Ka\! +'! C>;%-&'! NC>+K+=4';+>;)'! +>;.! G>! G%P;='! ('GG*G>%&'! ,*C>%;'! JRQb@! L>! .*&'B4&'..%1;! +'! C%7K"#>! .*44&%C'! GY'B4&'..%1;! +'! GYAK(>+,'&%;'!')!.)%C*G'!G>!FAI@!J%;.%9!GY%;,%O%)%1;!+'!C%7K"#>!.*44&%C'!4>&)%'GG'C';)!G>! FAI! %;+*%)'! 4>&! G'! F8_Ka! T3>1! ')! >G@9! "f\"U@! L'.! 5I09! V*%! .1;)! (1;;*.! 41*&! %;+*%&'! GY'B4&'..%1;! +'! C%7K"ff! ')! C%7K"fR9! .1;)! (>4>OG'.! +Y%;,%O'&! G>! FAI! ')! +'! 2><1&%.'&! G>! IAF! TN>C><>&(,%KF',&>;%!')!>G@9!"f\fU@!

L'!F8_Ka!>()%<'!+%&'()'C';)!GW'B4&'..%1;!+'!GWA#!*O%V*%)%;'!G%P>.'!D$I"9!4>&!G>!G%>%.1;! +*! (1C4G'B'! NC>+#hQ! .*&! .1;! 4&1C1)'*&@! HG! ';! &=.*G)'! ! GY*O%V*%)SG>)%1;! ')! +1;(! G>!

! R\! +=P&>+>)%1;! +'! 4R#9! ('G>! (1;(1*&>;)! ><'(! G>! 4&1P&'..%1;! +'! G>! FAI@! L'! F8_Ka! %;+*%)! GY'B4&'..%1;! +'! I+C"! T>;)>P1;%.)'! +'! 4R#U! G1&.! +'! G>! FAI! TJ&>]%! ')! >G@9! "f\fU@! L'! F8_Ka! %;+*%)!GW'B4&'..%1;!+*!2>()'*&!+'!)&>;.(&%4)%1;!N1BQ!V*%!'.)!;=('..>%&'!X!GY%;+*()%1;!+'!G>!FAI! Tp,>;P!')!>G@9!"f\">U@!

L'.! '22').! +*! F8_Ka! .1;)! <>&%=.! ';! 21;()%1;! +*! )S4'! ('GG*G>%&'! ')! +'.! (1;+%)%1;.@! L'! )S4'!('GG*G>%&'!')!GY';<%&1;;'C';)!(S)1]%;%V*'!+%()'!G>!;>)*&'!+'!G>!&=41;.'@!LW>O1;+>;('!')! G>!21;()%1;!+'.!+%22=&';).!G%P>;+.9!+'.!&=('4)'*&.!')!+'.!&=P*G>)'*&.!+*!F8_Ka!+=)'&C%;';)!G>! ;>)*&'! ')! GW%;)';.%)=! +*! .%P;>G! %;+*%)! 4>&! G'! F8_Ka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f\"U@!

L'!F8_Ka!'.)!%C4G%V*=!+>;.!G>!.*44&'..%1;!+'!GW>()%<%)=!>;)%K)*C1&>G'!+'.!LF9!+'.!^g9! +'.!;'*)&14,%G'.9!+'.!C1;1(S)'.!')!+'.!C>(&14,>P'.@!3'.!('GG*G'.!.1;)!(1;;*'.!41*&![1*'&! *;! &ZG'! %C41&)>;)! +>;.! G>! &=P*G>)%1;! +'! G>! 4&1P&'..%1;! )*C1&>G'@TL%! ')! >G@9! "ffcU@! $>;.! G'.! 4>),1G1P%'.! (>;(=&'*.'.9! G'! F8_Ka\! '.)! 4G*.! >O1;+>;)! V*'! G'! F8_Ka"! 1*! G'! F8_Ka#@! LW'B4&'..%1;!+*!F8_Ka\!'.)!+Y>%GG'*&.!.1*<';)!>*PC';)='!+>;.!G'!(>;('&!,*C>%;!Tt1[)1k%(lK 0&>P>9! "ff#U! TL'<S! >;+! D%GG9! "ffcU@! L1&.V*'! G'! F8_Ka! '.)! 'B4&%C=! ')! .=(&=)=! %;! <%<19! %G! '.)! .=V*'.)&=!+>;.!G>!C>)&%('!'B)&>('GG*G>%&'!TA3IU!')!2>%)!4>&)%!+W*;!(1C4G'B'!%;>()%2![*.V*WX!.1;! >()%<>)%1;! TN)1<'&! ')! >G@9! "ffdU@! :;'! 21%.! >()%<=9! G'! F8_Ka! .'! G%'! ><'(! G'! &=('4)'*&! F8_Ka! +'! )S4'! HH! TFa7HH9F8_Ka7HHU! ')! G'! G%P>;+! G%=! >*! Fa7HH! '.)! (>4>OG'! +'! )&>;.>()%<'&! '22%(>('C';)! G'! &=('4)'*&! +'! F8_Ka! +'! )S4'! +'! H! TFa7Hw! F8_Ka7\U! T$'&S;(]! >;+! p,>;P9! "ff#UTN,%! >;+! I>..>P*=9!"ff#U@!

L'! G%P>;+! +*! F8_Ka\! '.)! .*&'B4&%C=! +>;.! G'.! (>;('&.! +*! .'%;9! +*! (ZG1;9! +'! GW|.14,>P'9!+'!GW'.)1C>(9!+*!21%'9!+*!4>;(&=>.9!+*!41*C1;!')!+'!G>!4&1.)>)'@!3'4';+>;)9!G'.! C*)>)%1;.!')!G>!4'&)'!+'.!&=('4)'*&.!+*!F8_Ka!+'!)S4'!H!')!+'!)S4'!HH!1;)!=)=!+=)'()='.!+>;.! +'! ;1CO&'*B! (>;('&.@! L>! +=G=)%1;9! G>! C*)>)%1;! ')! G>! 4'&)'! +'! GY'B4&'..%1;! +'! NIJ$Q! >! =)=! &>441&)='!+>;.!G'!(>;('&!+'.!<1%'.!O%G%>%&'9!G'!(>;('&!+'!G>!<'..%'9!G'!(>;('&!+*!.'%;9!G'!(>;('&!

! R"! +*!(1G!+'!GW*)=&*.9!G'!(>;('&!+*!(ZG1;9!G'!(>;('&!+*!21%'9!G'!(>;('&!+'!GW%;)'.)%;9!G'!(>;('&!+'! GW|.14,>P'9! G'! (>;('&! ! +*! 41*C1;9! G'! (>;('&! +'! GW1<>%&'! ')! G'.! (>;('&.! 4>;(&=>)%V*'.@! L>! C*)>)%1;!1*!G>!4'&)'!+'!NIJ$"!>!=)=!+=)'()='!+>;.!G'!(>;('&!+*!(1G!+'!GY*)=&*.9!G'!(>;('&!+*! (ZG1;9!G'!(>;('&!+*!41*C1;!')!G'!(>;('&!+*!21%'@!3'4';+>;)9!NIJ$#!>!=)=!C>%;)';*'!+>;.!G>! 4G*4>&)! +'.! (>;('&.! (1CC*;.! T8&>+S! >;+! I>&]1k%)l9! "ff"U9! TL'<S! >;+! D%GG9! "ffcU9! T5%'&%'! >;+!I1.'.9!"ffcU@!

LA!F8_Ka!2><1&%.'!G'!+=<'G144'C';)!)*C1&>G@!L'!OG1(>P'!+'!G>!<1%'!+'!.%P;>G%.>)%1;!+*! F8_Ka!.4=(%2%V*'!+'.!LF!4'&C')!G>!P=;=&>)%1;!+W*;'!&=41;.'!%CC*;%)>%&'!'22%(>('!')!(>4>OG'! +W=&>+%V*'&! +'.! )*C'*&.! (,'l! G'.! .1*&%.! T81&'G%]! >;+! _G><'GG9! "ff\U! @! $>;.! G'! C%(&1K ';<%&1;;'C';)!)*C1&>G!G'.!.1*&('.!+'!F8_Ka!.1;)!C*G)%4G'.@!HG!>!=)=!C1;)&=!&=('CC';)!V*'! G'.!LF&'P!!3$Q!„!3$"R!„!=)>%';)!*;'!.1*&('!C>['*&'!+'!F8_Ka@!$Y>4&-.!('))'!=)*+'9!G'!F8_Ka! ;Y%;,%O'&>%)!4>.!G'!+=<'G144'C';)!+'!G>!414*G>)%1;!3FL!3$e!„9!C>%.!2><1&%.'&>%)!G'.!21;()%1;.! '22'()&%('.! +'.! 3FL! T3,';! ')! >G@9! "ffRU@! …! GW,'*&'! >()*'GG'9! *;! ('&)>%;! ;1CO&'! +W=)*+'.! 1;)! (G>%&'C';)!+=C1;)&=!V*'!G'!F8_K!a!41*<>%)!.*44&%C'&!G>!+%22=&';(%>)%1;!+'.!LF!(S)1)1B%V*'.! TJ,C>+l>+',! >;+! 71.';O'&P9! "ffRU9! T7>;P'.! ')! >G@9! \bedU@! L'! F8_Ka! 'C4u(,'! =P>G'C';)! GW'B4&'..%1;! +'.! P&>;lSC'! Jh59! +'.! 4'&21&%;'.9! +'! _>.L! ')! +'! GW%;)'&2=&1;KP>CC>! V*%! 2><1&%.';)!G>!(S)1)1B%(%)=!+'.!3FL!!TF,1C>.!>;+!I>..>P*=9!"ffRU9!T5%'&%'!>;+!I1.'.9!"f\fU@!!!

L'!F8_Ka!4'*)!.*44&%C'&!G>!+%22=&';(%>)%1;!+'.!GSC4,1(S)'.!F,\!')!F,"!')!2><1&%.'&!G>! +%22=&';(%>)%1;! +'.! LF&'P@! HG! %C4G%V*'! GY%;,%O%)%1;! +'.! ('GG*G'.! 3FL! F,\! ')! F,"9! )1*)! ';! 2><1&%.>;)! GW'B4>;.%1;! +'.! F&'P@! ! L'! F8_Ka! '.)! *;! 4*%..>;)! (,%C%1K>))&>()%2! 41*&! G'.! ^g9! G'.! C1;1(S)'.!')!G'.!I_@!HG!2><1&%.'!G>!+%22=&';(%>)%1;!+'.!C1;1(S)'.!';!C>(&14,>P'.@!L1&.V*W%G! '.)! 4&=.';)9! G'! F8_Ka! 2><1&%.'! G'! +=<'G144'C';)! +'.! (>;('&.! >..1(%=.! >*B! ('GG*G'.! ^g9! >*B! ;'*)&14,%G'.!')!>*B!I_!T5%'&%'!>;+!I1.'.9!"f\fU@!

L'! F8_Ka! .*44&%C'! GY>()%<%)=! (S)1GS)%V*'! +'.! ('GG*G'.! ^g! ')! %;,%O'! G'*&! .';.%O%G%)=! X! GW%;)'&2=&1;@!HG!&=4&%C'!GW'B4&'..%1;!+*!3ID!H!')!3ID!HH!+>;.!('&)>%;'.!414*G>)%1;.!('GG*G>%&'.@! L>!&=+*()%1;!+'!GY'B4&'..%1;!+*!3ID!K!H!+=4';+>;)'!+*!F8_Ka!';)&>~;'!G>!&=+*()%1;!+'!G>!GS.'! +'.! ('GG*G'.! )*C1&>G'.! 4>&! G'.! ('GG*G'.! ^g! TI>! >;+! ^%'+'&]1&;9! \bbRU9! T5%'&%'! >;+! I1.'.9! "f\fU@!L>!4&1+*()%1;!+'!F8_Ka!4>&!G'.!LF&'P!3$Q!„!3$"R!„!%;,%O'!G>!(S)1)1B%(%)=!('GG*G>%&'!+'.! ('GG*G'.! ^g! +=4';+>;)'! +*! &=('4)'*&! ^g8"$! ')! 2><1&%.'! G>! (&1%..>;('! ')! G>! +%..=C%;>)%1;! )*C1&>G'!T8,%&%;P,'GG%!')!>G@9!"ffR>UTNCS),!')!>G@9!"ffcU@!:;'!(1&&=G>)%1;!%;<'&.'!>!=)=!=)>OG%'!

! R#! ';)&'! G>! .=(&=)%1;! +'! F8_Ka\! ')! GW'B4&'..%1;! +*! &=('4)'*&! ^g8"$! (,'l! G'.! 4>)%';).! >))'%;).! +Y*;! (>;('&@! L>! 2>%OG'! 'B4&'..%1;! +*! &=('4)'*&! ^g8"$9! (1;)&%O*'! X! *;'! &=+*()%1;! +'! G>! (S)1)1B%(%)=!+'.!GSC4,1(S)'.!^g!')!4'&C')!G>!4&1P&'..%1;!+'!G>!C>G>+%'!TL''!')!>G@9!"ffQU@!!

_%;>G'C';)9!G'!F8_Ka!'.)!*;!2>()'*&!(,%C%1>))&>()%2!+'.!41GS;*(G=>%&'.!;'*)&14,%G'.@!HG! %;,%O'!G'*&!(>4>(%)=!X!.*44&%C'&!G>!(&1%..>;('!+'.!('GG*G'.!)*C1&>G'.!T7'%OC>;!')!>G@9!\bb\U@! :;'! 21;()%1;! 4&=+1C%;>;)'! +'.! ;'*)&14,%G'.! +>;.! G'! C%(&1';<%&1;;'C';)! )*C1&>G! '.)! G>! &'(1;;>%..>;('! ')! G>! +'.)&*()%1;! +'.! ('GG*G'.! )*C1&>G'.! 'B4&%C>;)! G'! _>.L@! LY'B4&'..%1;! +'! _>.L! '.)! *;'! (1C41.>;)'! %C41&)>;)'! +'! GY%;,%O%)%1;! +'.! (>;('&.9! V*%! >P%)! ';! %;+*%.>;)! +'.! .%P;>*B!+'!C1&)!+>;.!G'.!('GG*G'.!'B4&%C>;)!G'!&=('4)'*&!+'!_>.!TD>,;'!')!>G@9!\bbcU@!L'!F8_K a! OG1V*'! G>! +%22=&';)%>)%1;! +'.! C>(&14,>P'.! %;+*%)'! 4>&! GYH^_Km9! ('! V*%! %;,%O';)! G>! (>4>(%)=! +'.! C>(&14,>P'.! X! )*'&! '22%(>('C';)! G'.! ('GG*G'.! )*C1&>G'.! TD>>]K_&';+.(,1! ')! >G@9! \bbfU@! L'.! I$N3! .1;)! (1;;*'.! 41*&! u)&'! *;'! .1*&('! C>['*&'! +'! F8_K! a! ')! G'! &'(&*)'C';)! >((&*'! +'.!I$N3!'.)!';!(1&&=G>)%1;!><'(!GW>*PC';)>)%1;!+'!G>!4&1+*()%1;!+'!F8_Ka!%;!<%<1!TM>;P!')! >G@9!"ffe>U@!L'!F8_Ka!.)%C*G'!G'!&'(&*)'C';)!+'.!C1;1(S)'.9!+'.!C>(&14,>P'.9!+'.!^g9!+'.! $3!')!+'.!LF9!)1*)!';!%;,%O>;)!G'*&.!21;()%1;.!>;)%)*C1&>G'.!TL%!')!>G@9!"ffcU!Tt&l'.%;.]%!')!>G@9! "ffd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g$7h2G]K\U9! V*%! .1;)! 'B4&%C=.! 4&'.V*'! 'B(G*.%<'C';)! +>;.! G'.! ('GG*G'.! ';+1),=G%>G'.@! 3'.! +'&;%-&'.! 'B4&%C';)! ';! 1*)&'9! G'.! (1&=('4)'*&.! ;'*&14%G%;'K\! ')! ;'*&14%G%;'K"9! V*%! .'! G%';)! .=G'()%<'C';)! X! G>! 21&C'! \cR! +*! EA8_@! L'! EA8_! 2><1&%.'! >*..%! GY'B4&'..%1;! +'! _>.KL! .*&! G'.! ('GG*G'.! ';+1),=G%>G'.! ! ')! ('G>!

! RQ! 4&1<1V*'! GY>414)1.'! +'.! LF! 3$e„! G1&.! +*! 4>..>P'! +'! G>! O>&&%-&'! ';+1),=G%>G'! <'&.! G'! )%..*! )*C1&>G!TL''!')!>G@9!"f\RU@!

TNF-α

L'! F^_K`! TF*C1&! ;'(&1.%.! 2>()1&U! [1*'! *;! &ZG'! 4&1! ')! >;)%K)*C1&>G'! 4>&! &>441&)! >*! (1;)'B)'@! L'! F^_K`9! %;%)%>G'C';)! +=(1*<'&)! 41*&! .1;! >()%<%)=! >;)%)*C1&>G'9! >! =)=! C1;)&=! (1CC'! GW*;! +'.! 4&%;(%4>*B! C=+%>)'*&.! +'! GW%;2G>CC>)%1;@! H;+*%)! 4>&! *;'! G>&P'! P>CC'! +'! .)%C*G%.! 4>),1P-;'.9! G'! F^_K`! %;+*%)! +W>*)&'.! C=+%>)'*&.! +'! GW%;2G>CC>)%1;@! L'! F^_K`! '.)! =P>G'C';)!4&1+*%)!4>&!G'.!)*C'*&.!')!4'*)!>P%&!(1CC'!*;!4&1C1)'*&!';+1P-;'!+'!)*C'*&@!!

L'!F^_K`!'.)!*;'!(S)1]%;'!C*G)%21;()%1;;'GG'!V*%![1*'!*;!&ZG'!%C41&)>;)!+>;.!+%<'&.! =<=;'C';).! ('GG*G>%&'.! )'G.! V*'! G>! .*&<%'! ('GG*G>%&'9! G>! 4&1G%2=&>)%1;9! G>! +%22=&';(%>)%1;! ')! G>! C1&)@! L'! F^_K`! 'B'&('! .'.! 21;()%1;.! O%1G1P%V*'.! X! )&><'&.! GW>()%<>)%1;! +'! <1%'.! +'! .%P;>G%.>)%1;!+%.)%;()'.!)'GG'.!V*'!^_K]5!')!o^g@!^_K]5!'.)!*;!.%P;>G!>;)%K>414)1)%V*'9!)>;+%.! V*'!o^g!(1;)&%O*'!X!G>!C1&)!('GG*G>%&'!')!G'*&!O>G>;('!+=)'&C%;'!G>!&=41;.'!X!F^_K`@!

L'!F^_K`!>!+'*B!&=('4)'*&./!F^_7\!T4RRU!')!F^_7"!T4dRU@!L1&.!+'!G>!G%>%.1;!+*!F^_K`9! V*%! '.)! *;! ,1C1)&%C-&'! ;>)*&'G9! F^_7K\! 21&C'! *;! ,1C1)&%C-&'! 41*&! &'(&*)'&! G'! F7J$$! TF^_7K>..1(%>)'+!+'>),!+1C>%;U@!F7J$$!(1;.)%)*'!*;'!4G>)'21&C'!+'!&'(&*)'C';)!41*&!G'.! 4&1)=%;'.! >+>4)>)&%('.! (1CC'! 7H0! T&'('4)1&! %;)'&>()%;P! 4&1)'%;U9! ! F7J_K"! TF^_7K>..1(%>)'+! 2>()1&! "U9! _J$$! T_>.K>..1(%>)'+! +'>),! +1C>%;U! .'&<>;)! X! &'(&*)'&! G'.! C1G=(*G'.! (G=.! &'.41;.>OG'.!+'!G>!.%P;>G%.>)%1;!%;)&>('GG*G>%&'!41*&!>()%<'&!^_K]5!')!o^g@!!

L'!F^_K`!'.)!%C4G%V*=!+>;.!GY>;P%1P';-.'9!GW%;<>.%1;!')!G'.!C=)>.)>.'.!+'.!(>;('&.@!L'! F^_K`! 'B1P-;'! 1*! 4&1+*%)! 4>&! G'.! C>(&14,>P'.! >((=G-&'! G>! FAI! ')! >%;.%! (1;)&%O*'! X! G>! 4&1P&'..%1;!')!GY%;<>.%1;@!L'!F^_K`!>C=G%1&'!GY%;<>.%1;!+'.!(>;('&.!<%>!GY%;+*()%1;!+'.!II0!K! "9! #9! b9! \"9! `"a\! %;)=P&%;'! ')! +YH3JIK\! T5>)'.! >;+! I'&(*&%19! "ff#UT3,*>;P! ')! >G@9! "ffeU! H3JIK\!TIS'&.!')!>G@9!\bb"U@!!!!!!

! RR!

ICAM-1

o'! ! )&>%)'&>%.! G'.! (>&>()=&%.)%V*'.! +YH3JIK\TH;)'&3'GG*G>&! J+,'.%1;! I1G'(*G'U9! 4>&C%! G'.! +%22=&';)'.! C1G=(*G'.! %;+*%)'.! 4>&! F^_K`9! (1CC'! +>;.! G'! (>+&'! +'! ;1)&'! )&><>%G9! ;1*.! ><1;.!1O.'&<=!.1;!%;+*()%1;!G1&.!+*!)&>%)'C';)!><'(!G'!F^_K`@!

N)&*()*&'!! +YH3JIK\/! L'! P-;'! +YH3JIK\! T=P>G'C';)! (1;;*! .1*.! G'! ;1C! +'! 3$RQU! .'! )&1*<'!.*&!G'!(,&1C1.1C'!\b@!L>!4&1)=%;'!H3JIK\!'.)!*;'!4&1)=%;'!C'CO&>;>%&'!,>*)'C';)! PGS(1.SG='!+'!ef!X!\\Q!]$>!T.'G1;!G'!+'P&=!+'!PGS(1.SG>)%1;U@!HG!.'!(1C41.'!+'!(%;V!+1C>%;'.! 'B)&>('GG*G>%&'.9!*;!+1C>%;'!)&>;.C'CO&>;>%&'!')!*;'!V*'*'!%;)&>(S)14G>.C%V*'!(1*&)'!+'! "e! >(%+'.! >C%;=.! T<>;! +'! N)1G4'! >;+! <>;! +'&! N>>P9! \bbcU@! 3'))'! PGS(14&1)=%;'! +'! .*&2>('! ('GG*G>%&'!.'&)!+'!G%P>;+!41*&!G'.!a"K%;)=P&%;'.9!L_JK\!T3$\\>h3$\eU!')!I>(K\!T3$\\Oh3$\eU9! V*%! .1;)! 'B4&%C=.! 4>&! G'.! G'*(1(S)'.! TI>&G%;! >;+! N4&%;P'&9! \bedUT$%>C1;+! ')! >G@9! \bbfU9! ')! 41*&!G>!G'*(1.%>G%;'!T3$Q#U!'B4&%C='!4>&!G'.!LF!TLSC4,1(S)'!FU!T71.';.)'%;!')!>G@9!\bb\U@!!

AB4&'..%1;!+YH3JIK\/!H3JIK\!;Y'.)!4>.!'B4&%C=!+>;.!G'.!)%..*.!;1&C>*B!+*!('&<'>*9! +'.! ;'&2.! 4=&%4,=&%V*'.9! +*! 4>;(&=>.9! +'! GW1<>%&'9! +*! .'%;9! +'! GW*)=&*.9! +*! (1G! *)=&%;9! +'! G>! 4&1.)>)'9! +*! 41*C1;9! +*! G>&S;B9! +'! G>! C1'GG'! 1..'*.'9! +*! C*.(G'! .)&%=9! +*! (|*&9! ! +*! C=.1),=G%*C9! +'! GW1'.14,>P'9! +'! GW%;)'.)%;! P&uG'! 9! +*! (ZG1;! ')! +*! 21%'! TD>S'.! >;+! N'%P'G9! "ffbU@!AGG'!'.)!.*&'B4&%C='!+>;.!G>!&>)'!')!.*&!+%<'&.!)S4'.!+'!('GG*G'./!+'.!PG1O*G'.!OG>;(.9! +'.! 2%O&1OG>.)'.9! +'.! ('GG*G'.! ';+1),=G%>G'.9! +'.! ('GG*G'.! =4%),=G%>G'.! ')! +'.! ('GG*G'.! (>;(=&'*.'.@!L'.!+1CC>P'.!+>;.!G>!.)&*()*&'!+'!G>!C1G=(*G'!+YH3JIK\!1*!+'.!>;1C>G%'.!+'! .1;!'B4&'..%1;!';)&>~;';)!G'.!C=G>;1C'.9!G'.!)*C'*&.!GSC4,1+'.9!CS=G1+'.9!G'.!+=.1&+&'.! ;'*&1G1P%V*'.9! G'! &'[')! +Y1&P>;'.! )&>;.4G>;)=.9! GY%.(,=C%'9! GY>&)=&%1.(G=&1.'9! GY>.),C'! >GG'&P%V*'9!')({!T8&l'G'k.]>K7lSC1k.]>!>;+!0%')&l]1k%(l9!"ffQUTt%)]1k.]>!>;+!51&>k.]>9! "ffQU@!

7=P*G>)%1;! ')! 21;()%1;.! +YH3JIK\/! G3JIK\! .'! &')&1*<'! .1*.! 21&C'! +'! +%C-&'! X! G>! .*&2>('!+'.!('GG*G'.!,*C>%;'.@!N1;!&ZG'!4&%;(%4>G!'.)!GY%;+*()%1;!+Y*;'!%;)'&>()%1;!C';>;)!X! GY>+,=&';('! +'! +'*B! ('GG*G'.! T7'%GGS! ')! >G@9! \bbRU@! L>! V*'*'! %;)&>(S)14G>.C%V*'! +YH3JIK\! %;)'&>P%)! ><'(! +'.! 4&1)=%;'.! >..1(%='.! >*! (S)1.V*'G'))'! +Y>()%;'/! GY`K>()%;%;'9! GY'l&%;'9! GY>()%;'@! L'! &'C>;%'C';)! +*! &=.'>*! +Y>()%;'! .1*.KC'CO&>;>%&'! 4>&)%(%4'! =)&1%)'C';)! X! GY>()%<>)%1;! +'.! %;)=P&%;'.9! +1;)! G'! L_JK\! TLSC4,1(S)'! 2*;()%1;K>..1(%>)'+! >;)%P';! \U@!

! Rc! LY';P>P'C';)!+'.!C1G=(*G'.!+YH3JIK\!><'(!G'.!%;)=P&%;'.!C1O%G'.!';)&>~;'!G>!21&C>)%1;!+'.! 4')%).!1*!+'.!P&1.!>C>.!+'!L_JK\9!')!('G>!2><1&%.'!G>!(1;.1G%+>)%1;!+'!GY>+,=.%1;!T3>&4=;!')! >G@9!\bb"UTD'%.]>!')!>G@9!\bbeU@!

0G*.%'*&.! .%P;>*B! ')! 2>()'*&.! +'! )&>;.(&%4)%1;!/! G'! ^_Kr5! T;*(G'>&! 2>()1&! ]>44>KG%P,)K (,>%;K';,>;('&! 12! >()%<>)'+! 5! ('GG.U9! G'.! oJgTo>;*.! ]%;>.'U! h! NFJF! TN%P;>G! F&>;.+*('&.! >;+! J()%<>)1&.!12!F&>;.(&%4)%1;U9!GYH_^Km9!GYJ0K\!T>()%<>)1&!4&1)'%;K\U9!G'.!IJ0g!TI%)1P';K>()%<>)'+! 4&1)'%;! ]%;>.'U! ')! G'.! 0g3! T0&1)'%;! ]%;>.'! 3U! .1;)! %C4G%V*='.! +>;.! G>! &=P*G>)%1;! +YH3JIK\! T71'O*(]! >;+! _%;;'P>;9! \bbbUT7>,C>;! ')! >G@9! \bbbU@! HG! 'B%.)'! *;'! (1&&=G>)%1;! ';)&'! G'.! ;%<'>*B!>((&*.!+Y^_K]5!;*(G=>%&'!')!G>!+%C%;*)%1;!+YH3JIK\!+>;.!G'!(>.!+*!(>;('&!O*((>G@!A;! (1;.=V*';('!*;'!&=.%.)>;('!X!G>!(S)1)1B%(%)=!C=+%='!4>&!G'.!^g!')!G'.!LF!'.)!1O.'&<='!+>;.! ('.! )*C'*&.@! 0>&! (1;)&'9! ^_K]5! 4'*)! .'&<%&! (1CC'! *;! &=P*G>)'*&! 41.%)%2! ')! ;=P>)%2! +'! GW'B4&'..%1;! +YH3JIK\! .'G1;! G'.! .)%C*G%.@! 0>&! 'B'C4G'9! V*>;+! G'.! ('GG*G'.! )*C1&>G'.! DA4"! TD*C>;!'4%+'&C1%+!(>;('&!('GG.U!.1;)!)&>%)='.!><'(!G'!F^_K`!T)*C1&!;'(&1.%.!2>()1&!>G4,>U9! GW>*PC';)>)%1;! +'! GW'B4&'..%1;! +YH3JIK\! '.)! +%C%;*='! G1&.V*'! ^_K]5! '.)! OG1V*='@! 0>&! (1;)&'9!+>;.!G'!(>.!+'!('GG*G'.!)&>%)=.!><'(!GYH_^Km!T%;)'&2'&1;!P>CC>U9!GY'B4&'..%1;!+YH3JIK\! '.)! >*PC';)='! G1&.V*'! ^_K]5! '.)! OG1V*=@! A)! G'! )&>%)'C';)! +'.! ('GG*G'.! )*C1&>G'.! ><'(! G>! (1CO%;>%.1;! +'! F^_K`! ')! +YH_^Km! (1;+*%)! X! *;'! >()%<>)%1;! .S;'&P%V*'! +WH3JIK\@! 3'))'! (1CO%;>%.1;!>*PC';)'!=P>G'C';)!GY'B4&'..%1;!+*!3IDKH TC>[1&!,%.)1(1C4>)%O%G%)S!(1C4G'BU! .*&!G'.!('GG*G'.!)*C1&>G'.9!('!V*%!(1;+*%)!X!GW%;,%O%)%1;!+'!G>!21;()%1;!+'.!('GG*G'.!^g!To'k'))! ')!>G@9!"ff#U@!!

$Y>4&-.! 81&P1*G%.! ')! .'.! (1GG-P*'.9! GY%;,%O%)%1;! +'! ^_K]5! ;W'C4u(,'! 4>.! GW%;+*()%1;! +YH3JIK\!4>&!4R#!.*%)'!>*B!+1CC>P'.!+'!GWJ$^@!3'G>!C1;)&'!V*'!G>!&=P*G>)%1;!+YH3JIK\!4>&! 4R#!'.)!^_K]5K%;+=4';+>;)'@!J4&-.!G'!)&>%)'C';)!><'(!GY%;,%O%)'*&!.4=(%2%V*'!+'!4R#!/!0_FK`! 9T4%2%),&%;!`U!GY%;+*()%1;!+WH3JIK\!'.)!.*44&%C='@!A;!Cu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ff#U@!H3JIK\! '.)!.*&'B4&%C=!+>;.!G'.!('GG*G'.!.=;'.(';)'.9!G'.!)%..*.!‚P=.!TI%;>C%;1!')!>G@9!"ff"U9!')!4R#!

! Rd! '.)! >*..%! %C4G%V*=! +>;.! G'! 4&1('..*.! +'! <%'%GG%..'C';)! TFS;'&! ')! >G@9! "ff"U@! L>! .=;'.(';('! ('GG*G>%&'!')!G'!<%'%GG%..'C';)!4'*<';)!&'4&=.';)'&!*;!G%';!.*44G=C';)>%&'!';)&'!4R#!')!H3JIK \@!!

JGG%;P,>C! ')! .'.! (1GG-P*'.! 1;)! +=(&%)! G'! &ZG'! +YH3JIK\! +>;.! G>! C%P&>)%1;! +'.! G'*(1(S)'.@!LY';P>P'C';)!+YH3JIK\!+>;.!G'.!('GG*G'.!';+1),=G%>G'.!(1;+*%)!X!GW>()%<>)%1;!+'! +'*B!)S&1.%;'.!]%;>.'.!/!N&(!')!0S]"!T4&1G%;'K&%(,!)S&1.%;'!]%;>.'!"U@!L'.!21&C'.!>()%<'.!+'!('.! ]%;>.'.!.1;)!&'(&*)='.!>*B!.%)'.!+'!G%>%.1;!+WH3JIK\!')!%;+*%.';)!G>!4,1.4,1&SG>)%1;!+'!G>!EAK (>+,=&%;'! >*B! )S&1.%;'.! cRe! ')! d#\! (1&&'.41;+>;)! >*B! .%)'.! +'! G%>%.1;! +'! 4\"fK(>)=;%;'! ')! +'! aK(>)=;%;'@! J%;.%9! GY';P>P'C';)! +YH3JIK\! >O1*)%)! X! G>! +%C%;*)%1;! +'! G>! G%>%.1;! +'! 4\"fK (>)=;%;'!')!+'!aK(>)=;%;'!><'(!EAK(>+,=&%;'@!3'))'!4'&)'!+'!G%>%.1;!+'.!(>)=;%;'.!';)&>~;'! *;'! 4'&)'! G1(>G'! +'! GW%;)=P&%)=! +'.! [1;()%1;.9! ('! V*%! 2>(%G%)'! G'! 4>..>P'! 4>&>('GG*G>%&'! +'.! G'*(1(S)'.@! LW>()%<>)%1;! +'! 0S]"hN&(! ';+1),=G%>G9! >%;.%! V*'! G>! 4,1.4,1&SG>)%1;! +'! G>! EAK (>+,=&%;'! >*! McRe! ')! Md#\! .1;)! +1;(! ;=('..>%&'.! 41*&! G>! C%P&>)%1;! )&>;.';+1),'G%>G! +'.! G'*(1(S)'.!TJGG%;P,>C!')!>G@9!"ffdU@!

HG! S! >! >*..%! +'.! )&><>*B! V*%! +=(&%<';)! GY'B4&'..%1;! +YH3JIK\! (1CC'! *;! 2>()'*&! +'! C>*<>%.!4&1;1.)%V*'!+>;.!G'!(>.!+'.!(>;('&.@!N'G1;!('.!=)*+'.9!G'.!&=.%+*.!)S&1.%;'.!MQdQ!')! MQeR9!G1(>G%.=.!+>;.!G>!V*'*'!%;)&>(S)14G>.C%V*'!+'!GYH3JIK\9!.1;)!&'.41;.>OG'.!+*!(G%<>P'! +YH3JIK\! 4>&! +'.! 4&1)=>.'.! ')! ';)&>~;'! G>! 4&=.';('! +Y! H3JIK\.! TH3JIK\! .1G*OG'U! +>;.! G>! (%&(*G>)%1;! .>;P*%;'! TF.>]>+l'! ')! >G@9! "ffQU@! H3JIK\.! %;,%O'! ! G>! &=41;.'! %CC*;%)>%&'! ')! +%C%;*'! G>! C%P&>)%1;! +'.! G'*(1(S)'.! <'&.! G'.! )%..*.! 4=&%4,=&%V*'.@! L>! .=(&=)%1;! =G'<='! +YH3JIK\.!4>&!G'.!('GG*G'.!(>;(=&'*.'.!OG1V*'!G>!&'(1;;>%..>;('!+'!('.!('GG*G'.!4>&!G'.!LF!')! G'*&!4'&C')!+W=(,>44'&!>*!.S.)-C'!%CC*;%)>%&'@!$1;(9!<%>!('))'!%CC*;1.*44&'..%1;9!H3JIK \.! %;+*%)! G>! 4&1P&'..%1;! +*! (>;('&! ')! +'.! C=)>.)>.'.! T8&1),'S! ')! >G@9! \bbeU@! L'.! (1;(';)&>)%1;.! =G'<='.! +YH3JIK\.! (%&(*G>;)! 1;)! =)=! >..1(%='.! X! G>! 4&=.';('! +'! C=)>.)>.'.! ,=4>)%V*'.!+>;.!G'!(>;('&!+'!GW'.)1C>(9!+*!(ZG1;9!+*!4>;(&=>.9!+'!G>!<=.%(*G'!O%G%>%&'!')!X!*;'! 2>%OG'! .*&<%'! +>;.! G'! C=G>;1C'! C>G%;! TE'G%]1<>! ')! >G@9! \bbdU@! $>;.! G'! (>.! +'! +%<'&.'.! %;2G>CC>)%1;.9!+'.!%;2'()%1;.!')!+'.!C>G>+%'.!C>G%P;'.9!1;!&')&1*<'!>*..%!+'.!;%<'>*B!=G'<=.! +YH3JIK\.!+>;.!G'!.=&*C!+'.!4>)%';).@!

E1%(%!*;!>*)&'!C1+-G'!+=(&%<>;)!H3JIK\!(1CC'!*;!C>*<>%.!2>()'*&@!L'.!('GG*G'.!+'! )*C'*&.!.1G%+'.!<%>!I:3K\!TI*(%;K\U!.'!G%';)!X!H3JIK\!.*&!G'.!('GG*G'.!';+1),=G%>G'.@!3'))'!

! Re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ffdU!@! ! ! ! ! ! ! ! ! ! ! (;<=>?!Y!A!.E!T;<>ED;MG!D>EGBP?GJMDQCI;EI?!J?B!H?II=I?B!D=TM>EI?BK!

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hI>(K\! TC>(&14,>P'! >+,'.%1;! G%P>;+K\U! +'.! 0I^.! ><'(! H3JIK\! +'! )*C'*&! 4'&C')! G'! (&1..K G%;]%;P! +'.! G%P>;+.! ')! >()%<'! 0I^.! 41*&! G%O=&'&! +'.! =G>.)>.'.@! TAU! L'.! =G>.)>.'.! O&%.';)! G'.! O>&%-&'..! ';+1<>.(*G>%&'.! ')! ';+1GSC4,>)%V*'.! T_U! 4'&C'))>;)! G>! C%P&>)%1;! )&>;.';+1),=G%>G'! +'.! ('GG*G'.! )*C1&>G'.! ')!

GW'B4&'..%1;! =G'<='! +'! FJI T)*C1&K>..1(%>)'+! C>(&14,>P'U! T71G>;+! ')! >G@9! "ffdU@

!

!

! Rb!

B. LES VOIES DE SIGNALISATION

Documents relatifs