宮崎大学学術情報リポジトリ Title Author(s) プロテアーゼ活性化受容体2の生体内分布と動脈硬化発生 ・進展における役割 丸塚, 浩助; 浅田, 祐士郎; 畠山, 金太; 山下, 篤 Citation URL http://hdl.handle.net/10458/4259 Date of Issue 2006-05 Right Description 学術雑誌掲載論文の抜き刷りは出版社に著作権許諾が得 られていないため未掲載 平成16年度-平成17年度科学研究費補助金(基盤研究 (C))研究成果報告書 J EJ T-7--tt)!1ti~§!.i* 2 (1)~i*~~$ ~ Ib.ili~fe~ · • • r=~(t~&.J Sf~III1.-It 16590321 1iJf~"% : 00239154 1iJf~1f~% : 70202588 1iJf~"% : 60325735 1iJf~"% : 90372797 @JmJt F~~nmJt ~~t ¥PX: 1 6~lt 2,300 0 2,300 ¥PX: 1 7~l3t 1,300 0 1,300 3,600 0 3,600 tA~t ii:.'P 2 ------------------- l*-+'+-=~ /"~Plffl :)( ( 1 8 t>ffli) ---------------- Ll~() iVA 'I':.' ~~ ( 6 t>ffli) ---------------- 7 ~ ~ ( 2 t>ffli) ---------------- 7 1==1 Ll~() ------------------- ~~S) ------------------- 1O~ 12 ------------------- 10 ------------------- 11 ~ 12 ------------------- 3 13---- 1. Yamashita A, Furukoji E, Marutsuka K, Hatakeyama K, Yamamoto H, Tamura S, Ikeda Y, Sumiyoshi A, Asada Y: Increased vascular wall thrombogenici ty combined wi th reduced blood flow promotes occ lusive thrombus formation in rabbi t femoral artery. Arteriosclerosis, Thrombosis, and Vascular Biology, 2004;24(12) :2420-2424. 2. Harada-Shiba M, Takagi A, Marutsuka K, Moriguchi S, Yagyu H, Ishibashi S, Asada Y, Yokoyama S: Disruption of autosomal recessive hypercholesterolemia gene shows different phenotype in vitro and in vivo. Circulat ion Research, 2004; 95 (9) :945-952. 3. Nakamura R, Kato J, Kitamura K, Onitsuka H, Imamura T, Cao Y, Marutsuka K, Asada Y, Kangawa K, Eto T: Adrenomedull in administration immediately after myocardial infarction ameliorates progression of heart failure in rats. Circulation 2004;110(4): 426-431. 4. Kawamoto R, Hatakeyama K, Imamura T, ishikawa T, Date H, Shibata Y, Takenaga M, Asada Y, Eto T: Relation of C-reactive protein to restenosis after coronary stent implantation and to restenosis after coronary atherectomy. American Journal of Cardiology, 2004;94: 104-107. 5. Ishikawa T, Imamura T, Hatakeyama K, Date H, Nagoshi T, Kawamoto R, Matsuyama A, Asada Y, Eto T: Possible contribution of C-reactive protein within coronary plaque to increasing its own plasma levels across coronary circulation. American Journal of Cardiology, 2004;93:611---614. 6. Ishikawa T, Hatakeyama K, Imamura T, Ito K, Hara S, Date H, Shibata Y, Hikichi Y, Asada Y, Eto T: Increased adrenomedullin immunoreactivity and mRNA expression in coronary plaques obtained from patients with unstable angina. Heart, 2004 ;90: 1206-1210. 7. Tsuruda T, Kato], Cao YN, Hatakeyama K, Masuyama H, Imamura T, Ki tamura K, Asada Y, Eto T: Adrenomedullin induces matrix metalloproteinase-2 activity in rat aortic adventitial fibroblasts. 4 Biochemical and Biophysical Research Communications, 2004;325: 80-84. 8. Sato Y, Hatakeyama K, Yamashi ta A, Marutsuka K, Sumiyoshi A, Asada x.: Proportion of fibrin and platelets differs in thrombi on ruptured and eroded coronary atherosclerotic plaques in humans. 9. Heart, 2005; 91 (4) :526-530. Furukoji E, Matsumoto M, Yamashi ta A, Vagi H, Sakurai Y, Marutsuka ~ Hatakeyama K, Morishita K, Fujimura Y, Tamura S, Asada Y: Adenovirus-mediated transfer of human placental ectonucleoside triphosphate diphosphohydrolase to vascular smooth muscle cells suppresses platelet aggregation in vitro and arterial thrombus formation in vivo. Circulation, 2005;111(6) :808-815. 10. Hatakeyama K, Hao H, Imamura T, Ishikawa T, Shibata T, Fujimura Y, Eto T, Asada Y: Relation of CD39 to plaque instabil i ty and thrombus formation in directional atherectomy specimens from patients with stable and unstable angina pectoris. American Journal of Cardiology, 2005;95(5) :632-635. 11. Sun H, Koike T, Ichikawa T, Hatakeyama K, Shiomi M, Zhang B, Kitajima S, Morimoto M, Watanabe T, Asada Y, Chen YE, Fan J: C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance. American Journal of Pathology, 2005; 167 (4) : 1139-1148. 12. Tsuruda T, Kato J, Matsui E, Hatakeyama K, Masuyama H, Imamura T, Ki tamura K, Asada Y, Eto T: Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats. European Journal of Pharmacology, 2005; 508 (1-3) : 201-204. 13. Tsuruda T, Kato J, Hatakeyama K, Masuyama H, Cao YN, Imamura T, Kitamura K, Asada Y, Eto T: Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats. Cardiovascular Research, 2005; 65: 921-929. 14. Hoshiba Y, Hatakeyama K, Tanabe T, Asada Y, Goto S: Co-localization of von Willebrand factor with platelet thrombi, tissue factor and platelets wi th fibrin, and consistent presence of inflammatory cells in coronary thrombi 5 obtained by an aspiration device from patients with acute myocardial infarction. Journal of Thrombosis and Haemostasis, 2006;4 (1) : 114-120. 15. Nishihira K, Yamashi ta A, Tanaka N, Kawamoto R, Imamura T, Yamamoto R, Eto T, Asada Y: Inhibi tion of 5-hydroxytryptamine receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery. Journal of Thrombosis and Haemostasis. 2006;4(1) :247- 255. 16. Yamashita A, Sumi T, Goto S, Hoshiba Y, Nishihira K, Kawamoto R, Hatakeyama K, Date H, Imamura T, Ogawa H, Asada Y: Detection of von Wi llebrand factor and tissue factor in platelets-fibrin rich coronary thrombi in acute myocardial infarction. American Journal of Cardiology, 2006;97(1) :26-8. 17. Tsuruda T, Kato J, Hatakeyama K, Yamashita A, Nakamura K, Imamura T, Ki tamura K, Oni tsuka T, Asada Y, Eto T: Adrenomedullin in mast cells of abdominal aortic aneurysm. Cardiovascular Research, 2006; 70 (1) : 158 -164. 18. Kawamoto R, Yamashita A, Nishihira K, Furukoji E, Hatakeyama K, Ishikawa T, Imamura T, Itabe H, Eto T, Asada Y: Different inflanrnatory response and oxidative stress in neointimal hyperplasia after balloon angioplasty and stent implantation in cholesterol-fed rabbits. Pathology Research and Practice, 2006 (in press) 6 1. Marutsuka K, Hatakeyama K, Yamashi ta A, and Asada Y: Role of thrombogenic factors in the development of atherosclerosis. Journal of Atherosc 1eros i sand Thrombos is, 2005; 12 (1) : 1-8. 2. 1\t1Jltx, AiamWJ, 7~v/~T~0/ 13*** 3. ~: [~*5J'-f-~5J't£\$ ~im~~~~ 7~v/~T~0/~~~~)j-~~~~ 2004;62(9) :211-215. AiamllJ, mWfa:, ~ : [Vascular Biologyi6)~Jj.t~lfilf~. ~m*l ~~$I3"JJ!±Ii!i6) ~Jj.t~lfilf~ . ~m*~fnIJ 4. JL\lfilw~)j-t£\{-t~f*l 1\t1JItX, AiamJllJ, ~1~ti{~;6~JEa:'o C:, ~: ~TJL'.dn.lfm 2005; 6 (1) : 19-26. [lfilf~~~~~ToQ&Al lfilw~~fet ~'~*IH~~~;6~{@~~tLt~ ~, tM~ lfil?~{~k~* -1 /1::: 1:::"?'--~~J: 0-C1fiJmlJ~no C: ~bh-Cv \~To ~h~~~1tric:":' ~-c'~ ~i6)~~fet0-Cv \o~ -c' L J: -) i6) .dn.~ c!:: till 5. 2005; 13 (2) : 130-133. I\UJItX, 1tiamJllJ, Uffa, ~ : [~JiJID£{~tt¥(ACS)~JilMt*l 7° 7--~~fi&~~a~lv~~~ .dn.1f~~ 2005;6(2) :97-104. 6. l\t1JtX, iLiamJllJ, Urfa, ~ , {±WBBffl": [J1[lfil,tiJL\*,~2006l L\ C: ij[;g~lJJJl*7ij!{~ JiX.AJ;; c!:: ~mfl.J;; 2006; 35 (10) : 1089-1096 J 7. WI a: lJJJl*7ij!{~'tilfilf~~PX:ft~~j3ttolfilW~~{~~1~tiC: lfilmE~~--9- .dn.ti.dn.~~.15 13* 2006; 17 (1) : 29-37. 1. ~ : ~1lli~}!H~~To£iill¥J· ~*~~ Jiljfr~~~ ~ ft~~ lJJJl*7ijH~c: lfil/J\t)i . {~~~i~* ~~O)6'.>~;t;.»ljfll} .rftL1fl~.e-state of arts Ver.3, pp.320-323 2005 2. 1\t1JItX, AiamJllJ, ~: 7°7--~ 7 7°7-f-- C:.I. 0--:; 3 / ~ --, ~ T'~ j) /v V 1:::"~ --t± pp. 112-113 7 2005 .dn.~~Tl::"~- <*»11•• · V~~~? A) 1. Marutsuka K, Hatakeyama K, Yamashita A, Moriguchi S, Sato Y, Asada Y: Pathophysiology of thrombogenic event in acute coronary syndrome. The 36th Japan Atherosclerosis Society Annual Meeting. English Forum 2: Plaque instability: From molecular mechanisms to clinical applications (Fukuoka, 2004) ••) <-~ 1. Hatakeyama K, Marutsuka K, Yamashita A, Moriguchi S, Imamura T, Shibata Y, Fujimura Y, Asada Y: CD39 expression in human coronary atherosclerotic lesions. Xth Congress of the International Society of Hematology, Asian-pacific Division (Nagoya, 2004) 2. awtx, )II~-$J, Urf Ii, N~lffF, .i~, tt~~z, tt• • rt6, Iim:f>ti±iB "21/1'.~=, it~M, ~# : /'\Jv-/~i!fj:3J::aAT/ t-~Af~ O)m1:.~n~px:~~j:3't Q~11EJXr.t, CRP, ~{~A t:.~!-t ffi36[E] 13 *lb~1i~{t:'T:fr¥:f;Fj*,.g~ 3. (fifRiL t- VAO)~~ rWJ~~rfnJ£E*J[~fflJ., 2004) JW• •J.I-r, rr6*fk-r, *~ilfi, ~~tJ*:J.I, it_mill, ~, Jflf ~:Jb, ;p-a -R, .~mta :Autosomal recessive hyper-cholesterolemia (ARH) / '/ -7 7? t- y? A O)~JtfJT-ARH(:tLDLSt~{*l& tJ i6Jj.~~£\~;(p? m36[E] S *Ib~1i~{~'T:fr$:"~j*,.g~ (1ifRiL 2004) 4. aWj}:x, - ~: ~~1i~{t:m~~j:3'tQCD39/ecto-ATPDase m 9 @]rfil1fm~'1E~ 5. \ ~mO)~!i Of~Jl~" 2004) Hatakeyama K, Azuma Y, Hao H, Imamura T, Nishihira K, Kawamoto R, Shirai M, Ogawa H, Asada Y: Lack of association between Chlamydia pneumoniae infection and plaque instability or restenosis In coronary atherosclerotic lesion. m69@] S *fJtU!ft~~*,.g~ (~i~" 2005) 6. Hatakeyama K, Hao H, Imamura T, Ishikawa T, Shibata Y, Fujimura Y, Eto T, Asada Y: Relation of CD39 to plaque instability and thrombus formation in directional atherectomy specimens from patients wi th stable and unstable angina pectoris. 8 7. Nishihira K, Hatakeyama K, Imamura T, Shibata Y, Itabe H, Nakamura H, Yodoi], Ogawa H, Eto T, Asada Y: Thioredoxin and oxidized lipoprotein are increased in unstable plaque obtained by directional coronary atherectomy. m69[m S *~~~~¥t~ (f1i7~, 2005) 8. Hoshiba Y, Hatakeyama K, Asada Y, Goto S: Possible contributing role of tissue factor and activated platelets in the formation of occlusive fibrin-rich coronary thrombi. m69[EI1 S *~~~~¥t~ (f1i7~, 2005) 9. Tsuruda T, Kato ], Matsui E, Hatakeyama K, Masutyama H, Imamura T, Kitamura K, Asada Y, Eto T: Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats. m69@] S *~~~~¥t~ (f1i7~, 2005) 10. mwtx, 3JSJJlmz, iLDlb, WT II, .I:lnt~, ~ ~l1~:!ff~J=j3tt .:sChlamydia pneumonia ~~~=~\t \-cO)~~-t m94[m S *m~'T'ft~~ (tltl~, 2005) 9 : JEOOJJl* mJJJl*fi~1r:~t:t, J1[Ifn:t1/L*,~,· ~J;9rfn.l1~t~ · ~~O)t1{k ft~,~m,~ft~t~~§ I ~~=- T ~ ~ b~~, JEIEI0)J:.{ft~66b0*,~$0)£ti~ ft0~~C'tb ~, ~0)~~0)f!~ ~Jj ~ TI?JJ . i3~Yt0)1itflO:t~~0)l-;.ft Gf, 1±~a1~~tiEJ1JO)~~~ ft~ -CV \0 Jh~~ fi~1l1IE0)961:. . ii~~~ ---=>~ \-C, Jlt4\ rkJ»~~m~~fJXT 0rfn.11¥i~ff1J~!B~~iJ~itftif!b L- < ,:t~tU2JJ1~0)!j!~~!B~~Jt*C'tb0 ~ O)~~iJ~tb ~, Jhfl*fi~1r:961:.O)M':t¥m1it!~ L- -cv \0 0 ~~C'tb ~, n -cv \ftv \ L-iJ~t, Ifu.~~~!B~~iJ~mJJ~~fi~1r:~~~fJXT 0t~0)~~~!B,:t~<~ GiJ~'~ ~ fik ':t=-nj:C'~~, 0*lL.lEI-=r (TF) iJ~5~< mJJJIrIW~1r:~O)iijH~{=¥v\ 96m L--C:t3 ~, rfn.~~{mlJ!!l*O)§ I~~C'tb 7D7~:7llJniE'~{=¥~-C{mlJ!!l$'t1iJ~1Cii L-, =-n ~~et ~ rfn.f~~JJX:iJ~i€~~n, ~tlJamJJJIr~{,*ff0)96~~~*~< ~-9-T0 =- ~ ~w=I GiJ~'~ L--C ~ t::. (Atherosclerosis 1998, Thromb Haemost 1998, Circulation 2001) 0 j:t::., ~ 0) TF iJ~rfn.Hjz{mlJ!!l*i~5tt~~ 71E1-=r (FVI Ia) ~ TF/FVI Ia ~{*~~JJX:T 0 =- ~ ~~ et ~ -C, Ifill1-¥-¥1tff1J~OO~~~ ~~t L--CIfillJ"t&Jt *~~IEI-=rf§ ~ 0)5~j] ft!E1r:1l9-=r C' ~ 0 =- ~ ~ Y'Lv \ t:. L-t::. (Thromb Haemost 1996, 1997, Thromb Res 1999) 0 =-nGO)=- ~ et ~, JhJIr~~~96 m ~ n0 TF iJ~, FVI Ia ~fI' L-rfn.l1¥i1tff1J~lH~~O)W1!E~wlJ''* L-, Jh~~fi~1r:961:J~~-9- L--C ~ \0 =- ~ iJ~~p~~nt=-iJ~, TF/FV11a ~~{*O)¥i1tff1J~O)fFfflr~':t/f~C'~~t::.o Jlt~, ~ 0 /1::"/v~7yr~0)*.:t-o~:7"C'tb0 Protease-activated receptor 2(PAR2)iJ~ TF/FVIIa ~~{*~~ et ~ i~t11r: ~n0 =- ~ iJ~~~~n, fik b TF/FVIIa ~{*~~et 0rfn. 1f¥i1tff1J~!B~~O)W1!E~~ PAR2 iJ~~-9-T 0 =- ~ ~ Y'Lte L-t::. (Thromb Res, 2002) 0 L-ip L-, ~OO~~iIDC'O) TF/FVI 1a ~~{* ~ PAR2 ~ 0)f§1i1*91*:t3 et lfrfn.~~!j!~~!B~eIC'O)~~~!B,:t*t::/f ~JjC'tb00 j:t::., PAR2 O)*lL.rkJ71:fffT G, ~~~~ ~n -Cv \ft~ \O)iJ~~C'tb00 =- n GO)~~~~j: ;t, ~ T 0) 4 i~ ~AArt:1'rkJ 0) ~ t~~ ~m'f', *1iJfJ'E ~ii6b 0 0 1) PAR2 O)~~1:.{*rkJ (1:: ~, yr);A) 71:ffJ, 4'irH~, rfn.l1¥¥1tff1J~!B~eI:t3etlfrfn.~M$~!B~~ C'O) PAR2 0)96m~, !f:~~flJm{*~ fflv \-C~!B~~~"J:t3 et V,*J]fftt#I3"J,~~,gT 0 ~ ~ b~~, in situ hybridization yt:t3et If microdissection yt~m~ \-C71-=r1:4o/J~fIJ ~~~ET00 2) y r) ;A~~flJP9n~~~~:t3't 0 PAR2 O)f~IJ~~OOllJmljm{*~m~ \-C~~iET 0 0 j: t::., ~it1rt:19it~~:t3 et lf~it1rt:19Ifu.1f~~IH~ et ~, itit!E8*~!B~~~ ~ J: 0 Nn~mO) * 4Hf -t: /R ~ r.~F) -:l- 'Z. 'oJ o .I~\,,"c!:~L' 1.j 3) PAR2 J '/:7 7 r) ~ y r) ;A O)1'F~ ~ ~O)y r) ;A iJ ~ G{~ Gn0:rg.1€-¥-¥1tMJ~!B~~:t3 J: a itW!B~~~ffl~ \-C, ~!B~eIW15E~,~~fTV \ JhJl*fi~1r:~~JJX:~0)~~~~~iET00 4) TF/FVI 1a ~~{* ~ PAR2 ~ 0)~!B~~~iIDC'0)f§1i~1*0)~~iE~ ~!B~~rkJ't1f~{~Ji~f!~fJT T00 10 ~.~m~/~.~~~7N~~_: GFP"?r) A(J)~mlH~Pl~a.iH1C57BU6 ~~~, :':t~~~Bf~, :kJ]i!!ItJ}lrrdpG*ItJ~ ~~I6~'t-cT-{ P /* ~Mftt0 =- ~ ~~ J:: --=> -c, ~ L-v \.:c-r';v~f~ L-, ~[liH~1¥tET 0~~*lH~Pltj:~1 ~ t 0 1It7tlWjf,~~!frf~~Ifilf~(J)~{~~&arkJn~~~r--..(J)~«m*lH~Pllt * GFP ~JJJ~~aJijPl~l}~~~-t L-t:=.o ~~ IfnJ~~px:--rkJnl~~(J)--JJ!~~f(iffi-C~ ~ t:=., f1tPX:*lH~Pl~~W13Mt~~~H~[RJJJ: Iv ~';6) GFP ~~~1-Cd0--=> t:=.tf~, L-t:=.o IfnJ~(J) ~{l::~jS J:: arkJn~~ ~~, ¥{~*lH~Pl· rkJBt*lH~Pl(J)~~ ~~ L- t:=.*lH~Pl~ ~ tj: GFP ~JJJ~~IH~Pltj:~y~-cf1t PX:*IH~Pld0t:=. V) 1 %~~C'd0--=>t:=.o =-nG(J):'.. ~lPG, Ifilf~(J)~{l::~· ~~*~f1tPX:T0 *1H~Plt:t~1 ~ Iv ~';6)Ifil1t~;6~ GJQf/E L- -c ~ t:=. ¥{~Jffi*IH~Pl · rkJBt*lH~PlI6~GPX:0 =- ~ d0~ G;6~ ~ It. V), ~ftiilt**IH~Plt:t~l} L-t:=. ~ L- -c t~~b-r;6~C'd00 =- ~ ;6)~~nt:=.o : • ~mm C57BIJ6 "? r) A ~ /~ '/!7 !7 P A 5 {-It ~ (J) PAR2-KO "? r) A ~~jSv \-c, J:~C(J)j]t:t~ mv \-Crfn.f~~{l:: . rkJnl~~(J)~~~~~-t L-t:=.o PAR2-KO"? r) A ~~jSv \-C*TIfilt~~ ~{l:: . rkJn~~;6)~~" vftlrpH~d0--=>t:=.;6)1f~~t:t~B6b Gnlt.;6~--=>t:=.o -j], *~~ItJ~ rfj~~1Ifilt~jSJ:: arkJn~~ -=E--r';v ~f~(ATVB, 2004) L-, :. (J);fd ~jSv \-C, IfillJ,t&iU PAR2-KO ~? .A~;::toft Q.dn.~~H{~ 1JlJ*IJ5Zj]*~ ~ t~~PAR2 ~~J::0*IH~PlrkJ~!7"T;v{rot~1JlJ*IJT0~ ~:zG:n0 CD39 ~:'@J J1m!J!~1t0 ~rfn.t~~PX:~ ~ t~~rkJn~~~1JlJ*IJT0 =- ~ ~d0~ G;6~~~ L-t:=. (Circulation, 2005) itJlt••fU;:J: Q*.~* *fmM~~ ~ J:: V) : «.1\ L- t:=.1WjfW~I®f~l& V) ~Jj.?Rtii ~ m" \, 1:: r- ~lt#lJ~f~IJjS J:: L)\"? '/ A ~ ~jS, t 0 PAR2 (J):':t{:$:rkJ)j-;;fff ~t~~-t9JC' d0 0 0 ~ t:=., J:~c(J)llt~~¢:@' (~ J:: 0 *1H~Pl[RJ JJ: ~ ~ t ~~, 1L.\Jffi~~-=E--r';v~~jS't 0~@jt4t{l::(J)JJ:Ji(Circulation, 2004), ARH-KO"? '/ A ~~jS't 0LDLl& V) ~Jj.(J)~~~t~~-t L-t:=.(Circulation Res, 2004)0 .dn.~~~~~f'f: A{:$:(~jS't 0rfn.f~jS ~~, J:: a--e:n~~ {=¥ 5Ifilt~(J)~{l::/~n~~(J)*JlJJX~~BT 0 t:=.6b 1L.\JffiBl!~~f~ljm~lt#lJf~IH~jS" \-c, .{£Ct~ItJ~~~jS't0rfn.t~(J)*JlJJX~~~-t L-t:=.o --e(J)~*, 77--!71iBl§f~IJ-ct:t7 -17"~ /{~{lL(J)rfn.f~;6)~PX:~:n, {~IJ -ct:trfn.1J,*1R{~{lLC' d0 0;6)" \f:n(J)~-C (Heart, 2005) =- (J)~;~H:t, nl~~(J)px:*[E]f-~ ;6)~Jt~:nt:=.o t i1~d5'Ifilt~-c d0 0 ltJ~lIj!{l::JE:':t(J)£~~ L- -cIfillJ'*1R(J)Jj. lt.Gf, 7 (J Atheroscl Thromb, 2005) 11 It. 0 7"7--!7L)\GJv~ =- ~ ;6)d0 ~ G;6 ~ ~ It. --=> t:=.o rkJn~~*(J)~px:(J)fJ]WH~t:trkJ -17"~ /rfn.t~~~PX:T0i~I1!!I[E]f-(J)~-9 PAR2(1)7?.Aid J: 01:: ~ ~~idlt o~1*~~~(1)*tt : C57BL/6y? 7,jO J: -uPAR2 J '/ /;J 7? l' y? 7, J: ~ ~JtO)*J1I(~1*l&, 10%*/1/;7!J /jOJ:a4 %/'\7*/vA 7 /l/T'/'1' F~::J: 0~JEf.&0)/"77~ /WJ1jOJ:mJ1t~* __ I6~ GO)Olf'~J1~=jOtt\-C1~1JfJj.O)my?7,PAR2i~t1{~~7TF~=~rr0mnu.¥~jOJ:am ft&o)PAR2~::~rr0~~m{*~ffltt \t::§E~~m~-t~1T0 t::iJ~, fJIij~~=~~~i~ <, m{*jOJ:tJt;[Ifn.¥~O)y? 7,*__ ~::jO't0§E~~I¥J~m~::~L-Ctt 'ltv ':' ~ iJ~~;t G ~ t::, JEf.& 6 a~rf:l~U-NO)iftJ~1~IJ J: ~ ~Jt~~~1*1& L, ¥WWJ6tf'~tJJJ1'::jO't 0 §E~li,~~::lPJt1jH::~~-tLt::iJ~, :w:~1tJf1J*,lHij§· r~{~1fl:Bt~::9E~~~~600 bO)O), PAR2 O)1R'±f~A~ ~i~€!J1iJ~~/t0 -CjO ~ f~fJH1~::z L <, y? 7, [PJf~t ~~/t*,lHij§~tE~ ht::o ~te L1~/tl6 ~0 t:: o 1t-"7 ? .A ~~id It 0 *ttLltv: ~9E:ljj5eMK~jH¥~M~£\~~ vft~~t~fflv\ GFPy? 7,O)'ft.lHij§~, t1H1 C57BL/6~::mtf.&, -}-1' t1 /*&t!I~t~::-CIfn.t~/Nnlij~~T,;v~1~ L, 1fnJ~O)%Mt{~ /Nn~ij~~::M-9-T 0*,lHij§0)!fB=tt~[PJJE Lt::o fl·L~:'±.~1i'C£f.&, -}-l' t1 /*iit!lf.& 4 ~ § ~ =jt:J'tlWj~r~ =GFP~JJ1~1jlHij§O)M-9-~~~1 L t::iJ~, rRJ1f~{ft~0)'ft~E8 ~FP~JJ1~1 *,lHij§~i~Y~~::&~ ~, 'l~ Iv ~'M~ Lltv \=. ~ iJ~lb~ GI6~~ It0t:: o (~ffiJ)(1'FJJX:ep) 12
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