Results: In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression

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(1)pISSN : 2093-582X, eISSN : 2093-5641 J Gastric Cancer 2016;16(2):85-92  http://dx.doi.org/10.5230/jgc.2016.16.2.85. Original Article. Clinicopathological Significance of Elevated PIK3CA Expression in Gastric Cancer Si-Hyong Jang, Kyung-Ju Kim, Mee-Hye Oh, Ji-Hye Lee, Hyun Ju Lee, Hyun Deuk Cho, Sun Wook Han1, Myoung Won Son1, and Moon Soo Lee1 Departments of Pathology and 1General Surgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea. Purpose: PIK3CA is often mutated in a variety of malignancies, including colon, gastric, ovary, breast, and brain tumors. We investigated PIK3CA expression in gastric cancer and explored the relationships between the PIK3CA expression level and clinicopathological features as well as survival of the patients. Materials and Methods: We examined PIK3CA expression in a tissue microarray of 178 gastric adenocarcinomas by immunohistochemistry and reviewed patients’ medical records. Results: In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression. Overexpression of PIK3CA was correlated with low grade differentiation (P=0.001), frequent lymphatic invasion (P=0.032), and high T stage (P=0.040). Patients with positive PIK3CA staining were more likely to display worse overall survival rate than those with negative PIK3CA staining, as determined by Kaplan-Meier survival analysis with log-rank test (P=0.047) and a univariate analysis using the Cox proportional hazard model (hazard ratio=1.832, P=0.051). Conclusions: Elevated PIK3CA expression was significantly correlated with tumor invasiveness, tumor phenotypes, and poor patient survival. Key Words: PIK3CA; Stomach neoplasms; Immunohistochemistry. IBMGPGHBTUSJDDBODFSQBUJFOUTBSFOPUDVSFE#PUIFOWJSPONFOUBM. Introduction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orrespondence to: Moon Soo Lee Department of General Surgery, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea Tel: +82-41-570-3628, Fax: +82-41-571-0129 E-mail: msslee@schmc.ac.kr Received December 21, 2015 Revised March 30, 2016 Accepted April 14, 2016. 1*,QBUIXBZDPNQPOFOUT TVDIBTUIFSFDFQUPSUZSPTJOFLJOBTF HFOFT &('3 )&3 ,*5 15&/ 1*,$" BOE",51*,JT BIFUFSPEJNFSDPNQSJTJOHPGBOL%BSFHVMBUPSZTVCVOJUBOEB L%BDBUBMZUJDTVCVOJUUIBUQPTTFTTBOFO[ZNBUJDBDUJWJUZ5P EBUF GPVSJTPGPSNTPG1*,DBUBMZUJDTVCVOJU    BOE IBWF. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyrights © 2016 by The Korean Gastric Cancer Association. www.jgc-online.org.

(2) 86 Jang SH, et al.. CFFOJEFOUJGJFE"NPOHUIFTF UIFHFOFFODPEJOHUIFJTPGPSN DBUBMZUJDTVCVOJU 1*,$" Q XBTGPVOEUPCFGSFRVFOUMZ. SFWJFXFE1BUJFOUTXIPSFDFJWFEOFPBEKVWBOUDIFNPUIFSBQZBOE. NVUBUFEPSBNQMJGJFE MFBEJOHUPUIFBDRVJTJUJPOPGPODPHFOJD. TUVEZ$BTFTXJUIOPUJTTVFTBNQMFTBWBJMBCMFXFSFBMTPFYDMVEFE. PSIBEPUIFSDSJUJDBMNFEJDBMDPOEJUJPOTXFSFFYDMVEFEJOUIJT. . QSPQFSUJFTPSJODSFBTFEUVNPSBHHSFTTJWFOFTT 1*,$"NVUB UJPOBOEBNQMJGJDBUJPOJOHBTUSJDDBODFSIBWFBMTPCFFOEFTDSJCFE JOQBSUJDVMBS UIFBNQMJGJDBUJPOPG1*,$"JTGSFRVFOUMZPCTFSWFE . JOHBTUSJDBEFOPDBSDJOPNB. 2. Tissue microarray construction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mmunohistochemical staining and assessment. IVNBOHBTUSJDDBODFSUJTTVFVTJOHJNNVOPIJTUPDIFNJTUSZ8F FWBMVBUFEUIFSFMBUJPOTIJQTCFUXFFO1*,$"FYQSFTTJPOMFWFM. 'PS1*,$"JNNVOPIJTUPDIFNJTUSZ 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aterials and Methods. GPSBOUJHFOSFUSJFWBM5IFTFDUJPOTXFSFTUBJOFEXJUIBEJMV UJPOPGSBCCJUQPMZDMPOBMBOUJ1*,$"BOUJCPEZ )1". 1. Patients and specimens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⾘ UP UP . UPDPOGJSNEJBHOPTFT5IFDMJOJDPQBUIPMPHJDBMWBSJBCMFTPGUIF. BOE ⾚ *OUFOTJUZPGUIFJNNVOPTUBJOJOHXBTTDPSFEBT. QBUJFOUT JODMVEJOHBHF TFY UVNPSTJ[F UVNPSMPDBUJPO JOWBTJPO. GPMMPXT OFHBUJWF

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(6) 87 High PIK3CA Expression in Gastric Cancer. A. B. C. D. Fig. 1. Representative PIK3CA immunohistochemical staining images of gastric cancers (×400) exhibiting intensity score of 0 (A), 1 (B), 2 (C), or 3 (D).. A. B. C. Fig. 2. (A, B) Normal gastric mucosa, which was used as a negative control, displayed absence of PIK3CA staining (A) or weak PIK3CA staining (B) (×200). (C) Positive PIK3CA staining in tumor glands and negative staining in the adjacent non-tumorous gastric mucosa (×200).. TDPSFTPGⴎXFSFDPOTJEFSFEQPTJUJWF'PSOFHBUJWFDPOUSPMT . 4. Statistical analysis. OPSNBMHBTUSJDNVDPTBDPSFTXFSFJODMVEFEJOUIF5.". "MMTUBUJTUJDBMBOBMZTFTXFSFQFSGPSNFEVTJOHUIF1"48WFS. CMPDLT1*,$"JNNVOPSFBDUJWJUZTDPSFPGUIFTFDPSFTSBOHFE. TUBUJTUJDBMTPGUXBSF *#.$P "SNPOL /: 64" 5IF. GSPNUP"EEJUJPOBMMZ OPOUVNPSPVTNVDPTBBEKBDFOUUP UIFUVNPSDPSFTIPXFEOPJNNVOPSFBDUJWJUZPSXFBL1*,$".  UFTUGPSMJOFBSUSFOETBOE'JTIFS’TFYBDUUFTUXFSFVUJMJ[FEUP EFUFSNJOFUIFSFMBUJPOTIJQTCFUXFFO1*,$"FYQSFTTJPOBOE. QPTJUJWFTUBJOJOHJODPOUSBTUXJUIUIFUVNPSHMBOET 'JH . DMJOJDPQBUIPMPHJDBMGFBUVSFTPGUIFQBUJFOUT4VSWJWBMDVSWFTXFSF. .

(7) 88 Jang SH, et al.. Table 1. Correlations between PIK3CA expression and various clinicopathological features in gastric cancer patients. Gender Male Female Age (yr) <55 ≥55 Site Upper Middle Lower AJCC stage I/II III/IV Tumor depth* T1/T2 T3/T4 LN metastasis Absent Present Distant metastasis Absent Present WHO classification WD/MD PD/Mucinous Lymphatic invasion Absent Present Vascular invasion Absent Present Perineural invasion Absent Present Lauren classification Intestinal Diffuse Mixed Ming classification Expanding Infiltrative. $PYQSPQPSUJPOBMIB[BSETSFHSFTTJPONFUIPEUPDPNQBSFEJGGFS. PIK3CA expression Negative. Positive. 6OJWBSJBUFBOENVMUJWBSJBUFBOBMZTFTXFSFQFSGPSNFEVTJOHUIF FODFTJOPWFSBMMTVSWJWBM 04 CFUXFFOQBUJFOUTVCHSPVQT1⾘. P-value. XBTDPOTJEFSFETUBUJTUJDBMMZTJHOJGJDBOU. 0.289 127 51. 44 (66.7) 22 (33.3). 83 (74.1) 29 (25.9). 57 121. 27 (40.9) 39 (59.1). 30 (26.8) 82 (73.2). Results 0.051. 1. PIK3CA expression was correlated with clinicopathological features of the patients *OUIFDVSSFOUTUVEZ QPTJUJWF1*,$"TUBJOJOHXBTPCTFSWFE. 0.182 24 28 126. 4 (6.1) 14 (21.2) 48 (72.7). JOHBTUSJDDBODFSQBUJFOUT 1*,$"PWFSFYQSFTTJPO. 20 (17.9) 14 (12.5) 78 (69.6). XBTTJHOJGJDBOUMZDPSSFMBUFEXJUIGSFRVFOUMPXHSBEFEJGGFSFOUJB 0.170. 107 71. 44 (66.7) 22 (33.3). 63 (56.3) 49 (43.8). 90 88. 40 (60.6) 26 (39.4). 50 (44.6) 62 (55.4). MBUFSPOTFUBHF 1 IPXFWFS UIFTFDPSSFMBUJPOTXFSFOPU. 50 (44.6) 62 (55.4). 64 (37.0) 2 (40.0) 14 (21.2) 52 (78.8). 5BCMFTVNNBSJ[FTUIFDPSSFMBUJPOTCFUXFFO1*,$"FYQSFT. 49 (43.8) 63 (56.3) 0.032. 92 86. 41 (62.1) 25 (37.9). 51 (45.5) 61 (54.5). 160 18. 61 (92.4) 5 (7.6). 99 (88.4) 13 (11.6). .JOHDMBTTJGJDBUJPO 1 MZNQIOPEFNFUBTUBTJT 1 BOEUIFQSFTFODFPGWBTDVMBSPSQFSJOFVSBMJOWBTJPO 1 . 109 (63.0) 3 (60.0) 0.001. 63 115. TUBUJTUJDBMMZTJHOJGJDBOU/PTJHOJGJDBOUBTTPDJBUJPOTXFSFGPVOEGPS PUIFSDMJOJDPQBUIPMPHJDBMQBSBNFUFST JODMVEJOHTFY 1 UIF. 0.891 173 5. &MFWBUFE1*,$"FYQSFTTJPOXBTBMTPNPSFMJLFMZUPCFPC TFSWFEJOUIFVQQFSUIJSEPGUIFTUPNBDI 1 BOEEJTQMBZ. 0.202 36 (54.5) 30 (46.5). IJTUPMPHZPGUIF-BVSFODMBTTJGJDBUJPO 1 MZNQIBUJDJOWB TJPO 1 BOEBEWBODFE5TUBHF Q5PSNPSF1 . 0.040. 86 92. UJPO XFMMNPEFSBUFMZEJGGFSFOUJBUFE1 JOUFTUJOBMUZQF. TJPOBOEUIFDMJOJDPQBUIPMPHJDBMQBSBNFUFSTPGUIFQBUJFOUT. 2. Survival analysis "TJHOJGJDBOUDPSSFMBUJPOCFUXFFO1*,$"PWFSFYQSFTTJPO BOEQPPSTVSWJWBMXBTGPVOEVTJOHUIF,BQMBO.FJFSTVSWJWBM. 0.389 1.0. 0.863 139 39. 52 (78.8) 14 (21.2). 87 (77.7) 25 (22.3). 105 62 11. 30 (45.5) 32 (48.5) 4 (6.1). 75 (67.0) 30 (26.8) 7 (6.3). 0.012. 0.512 51 127. 17 (25.8) 49 (74.2). Low PIK3CA expression. 0.8. 34 (30.4) 78 (69.6). Values are presented as number only or number (%). AJCC = American Joint Committee on Cancer; LN = lymph node; WHO = World Health Organization; WD = well differentiated; MD = moderately differentiated; PD = poorly differentiated. *Classification according to the standard of AJCC staging system.. Overall survival. Parameter. Number of case. HFOFSBUFEVTJOHUIF,BQMBO.FJFSNFUIPEXJUIMPHSBOLUFTU. 0.6. High PIK3CA expression. 0.4 0.2 P=0.047. 0 0. 20. 40 60 Months after surgery. 80. 100. Fig. 3. Survival curve of the low PIK3CA expression group (n=112) and high PIK3CA group (n=66) as assessed by Kaplan-Meier survival analysis with log-rank test..

(8) 89 High PIK3CA Expression in Gastric Cancer. Table 2. Univariate survival analysis of factors associated with overall survival Overall survival Parameter Hazard ratio (95% CI). P-value. Gender (male versus female). 0.042 (1.175~4.292). 0.014. Age (<55 versus ≥55). 0.670 (0.393~1.142). 0.141. Tumor depth (T3/T4 versus T1/T2). 9.370 (4.760~18.342). <0.001. LN metastasis (present versus absent). 7.815 (3.974~15.370). <0.001. Distant metastasis (present versus absent). 7.214 (2.799~18.589). <0.001. WHO classification (PD/mucinous versus WD/MD). 1.487 (0.865~2.557). 0.151. Lymphatic invasion (present versus absent). 6.902 (3.748~12.712). <0.001. Vascular invasion (present versus absent). 5.897 (3.308~10.514). <0.001. Perineural invasion (present versus absent). 5.681 (3.455~9.340). <0.001. Lauren classification (diffuse/mixed versus intestinal). 1.885 (1.040~2.730). 0.034. Ming classification (infiltrative versus expanding). 1.818 (0.991~3.335). 0.054. PIK3CA expression (high versus low). 1.832 (0.998~3.361). 0.051. LN = lymph node; WHO = World Health Organization; PD = poorly differentiated; WD = well differentiated; MD = moderately differentiated; CI = confidence interval.. Table 3. Multivariate survival analysis of factors associated with overall survival Overall survival Parameter Hazard ratio (95% CI). P-value. Gender (male versus female). 0.599 (0.289~1.243). 0.169. Tumor depth (T3/T4 versus T1/T2). 3.068 (1.241~7.581). 0.015. LN metastasis (present versus absent). 1.463 (0.361~5.928). 1.463. Distant metastasis (present versus absent). 2.117 (0.671~6.681). 0.201. Lymphatic invasion (present versus absent). 2.339 (0.615~8.892). 0.212. Vascular invasion (present versus absent). 2.883 (1.448~5.740). 0.003. Perineural invasion (present versus absent). 2.548 (1.287~5.046). 0.007. Lauren classification (diffuse/mixed versus intestinal). 1.598 (0.856~2.983). 0.141. PIK3CA expression (high versus low). 1.369 (0.725~2.582). 0.333. LN = lymph node; CI = confidence interval.. BOBMZTJTXJUIMPHSBOLUFTU1BUJFOUTUIBUEJTQMBZFEQPTJUJWF1*,. NVMUJWBSJBUFBOBMZTJT 5BCMF . $"TUBJOJOHIBEXPSTF04UIBOUIPTFXJUIOFHBUJWF1*,$" TUBJOJOH 1'JH 5PGVSUIFSFWBMVBUFUIFQSPHOPTUJD. Discussion. JNQMJDBUJPOTPG1*,$"FYQSFTTJPOJOHBTUSJDDBODFST BVOJWBSJ BUFBOBMZTJTVTJOHUIF$PYQSPQPSUJPOBMIB[BSESFHSFTTJPONPEFM. 1*,JTBDPNQPOFOUPGUIF1*,TJHOBMJOHQBUIXBZUIBU. XBTQFSGPSNFE*OUIFVOJWBSJBUFBOBMZTJT QBUJFOUTXJUIQPTJUJWF. QMBZTDSVDJBMSPMFTJOUIFSFHVMBUJPOPGDFMMQSPMJGFSBUJPO TVSWJWBM . 1*,$"TUBJOJOHXFSFNPSFMJLFMZUPEJTQMBZSFEVDFE04DPN. BOEBEIFTJPODBQBDJUZ BOEJTGSFRVFOUMZVQSFHVMBUFEJOIVNBO. QBSFEUPUIPTFJOUIF1*,$"OFHBUJWFHSPVQ 1IB[BSE. DBODFST 1*,$" FODPEJOHUIFQTVCVOJUPG1*, JT. SBUJP5BCMF /PTJHOJGJDBOUEJGGFSFODFTJO04XFSF. MPDBUFEPODISPNPTPNFRBOENVUBUJPOTPGUIJTHFOFBSF. GPVOECFUXFFO1*,$"QPTJUJWFBOEOFHBUJWFHSPVQTVTJOHB. DPNNPOJOWBSJPVTNBMJHOBOUUVNPST JODMVEJOHDPMPO HBTUSJD .

(9) 90 Jang SH, et al.. PWBSZ CSFBTU BOECSBJOUVNPST *OHBTUSJDDBODFS NBOZ. DPMPSFDUBMDBODFSTUVEZBMTPSFQPSUFE1*,$"PWFSFYQSFTTJPOJO. TUVEJFTIBWFCFFOQFSGPSNFEUPFWBMVBUFUIFSPMFPGTPNBUJD. TQFDJNFOTXJUIIJHIHSBEFIJTUPMPHZBOENVDJOPVTBEFOPDBS. 1*,$"NVUBUJPOT CVUUIFTFTUVEJFTGPDVTFEMFTTPOUIFBCFSSBOU. DJOPNBNPSQIPMPHZ *ODPOUSBTUUPQSFWJPVTTUVEJFTJOPUIFS. PWFSFYQSFTTJPOPG1*,$")PXFWFS TJHOJGJDBODFPG1*,$". PSHBOT XFPCTFSWFE1*,$"PWFSFYQSFTTJPOJODBSDJOPNBTXJUI. PWFSFYQSFTTJPOJOPUIFSNBMJHOBOUUVNPST JODMVEJOHCSFBTU . MPXHSBEFIJTUPMPHZ XFMMNPEFSBUFMZEJGGFSFOUJBUFE1 . FTPQIBHFBMBOEDPMPSFDUBMDBODFST IBTCFFOFWBMVBUFECZJNNV. 5IJTUSFOEXBTBMTPPCTFSWFEXIFOBTTPDJBUJPOCFUXFFOUIF. . OPIJTUPDIFNJTUSZ. *ODSFBTFE1*,$"JNNVOPSFBDUJWJUZIBT. -BVSFODMBTTJGJDBUJPOBOE1*,$"FYQSFTTJPOXBTEFUFSNJOFE. CFFOJNQMJDBUFEGPSQPPSQSPHOPTJTBOENVMUJESVHSFTJTUBODFJO. 8FPCTFSWFEQPTJUJWF1*,$"TUBJOJOHJOJOUFTUJOBMUZQFBE. PUIFSDBODFST TVHHFTUJOHBQSPNJTJOHVTFPG1*,$"FYQSFTTJPO . FOPDBSDJOPNBT BOEOFHBUJWFTUBJOJOHJONJYFEBOEEJGGVTF. BTBTTFTTFECZJNNVOPIJTUPDIFNJTUSZ BTBDBODFSCJPNBSLFS . UZQFDBSDJOPNBT 1 5IF-BVSFODMBTTJGJDBUJPOTVCEJWJEFT. 'VSUIFSNPSF BSFDFOUTUVEZUIBUFWBMVBUFEB1*,$"NVUB. HBTUSJDDBODFSTJOUPEJGGVTFBOEJOUFTUJOBMUZQFTCBTFEPOUIFJS. UJPOJOFTPQIBHFBMDBODFSSFWFBMFEUIBU1*,$"PWFSFYQSFTTJPO . NPSQIPMPHZ*ODPOUSBTU 5BOFUBMSFQPSUFEBNPMFDVMBS. EFUFSNJOFECZJNNVOPIJTUPDIFNJTUSZ DPVMECFVUJMJ[FEBTBO. DMBTTJGJDBUJPOPGHBTUSJDDBODFSTCBTFEPOUIFHFOFFYQSFTTJPO. JOEFQFOEFOUGBDUPSUPQSFEJDUIJHIMPDBMSFDVSSFODF5PUIFCFTU. QBUUFSOT*OUIFJSTUVEZ NFTFODIZNBMBOEQSPMJGFSBUJWFUZQFT. PGPVSLOPXMFEHF UIFDVSSFOUTUVEZJTTFDPOEUPSFQPSU1*,$". XFSFBTTPDJBUFEXJUIEJGGVTFBOEJOUFTUJOBMUZQFBEFOPDBSDJOP. FYQSFTTJPOVTJOHJNNVOPIJTUPDIFNJTUSZBOEGJSTUUPEFTDSJCFUIF. NBT SFTQFDUJWFMZ'VSUIFSNPSF BSFDFOUTUVEZSFWFBMFEUIBUFBDI. TJHOJGJDBODFPG1*,$"PWFSFYQSFTTJPOGPSHBTUSJDDBODFSQBUJFOU. -BVSFODMBTTJGJDBUJPOTVCUZQF EJGGVTF NJYFE BOEJOUFTUJOBM FY. TVSWJWBM. IJCJUFEBVOJRVF%/"NFUIZMBUJPOTJHOBUVSFEVSJOHFBSMZHBTUSJD. *OBOJOWJUSPTUVEZVTJOHBUPOHVFDBODFSDFMMMJOF JOIJCJUJPO. DBSDJOPHFOFTJT5IFTFGJOEJOHTTVHHFTUFEUIBUUIFNPSQIPMPHJ. PG1*,$"FYQSFTTJPOXBTTIPXOUPTVQQSFTT15&/BOE"LU. DBMDIBSBDUFSJTUJDTPGHBTUSJDDBODFSBSFJOEVDFECZBWBSJFUZPG. QIPTQIPSZMBUJPOT SFTVMUJOHJOEFDSFBTFEQSPMJGFSBUJWFBDUJWJUZBOE. VOJRVFHFOFUJDPSFQJHFOFUJDBMUFSBUJPOT5IFSFGPSF XFDPODMVEFE. JOWBTJWFOFTTBOEJODSFBTFEESVHTFOTJUJWJUZ*OHBTUSJDDBODFS. UIBUEJGGFSFOU1*,$"FYQSFTTJPOMFWFMTBNPOHUIFIJTUPMPHJDBM. DFMMMJOFT LOPDLEPXOPG1*,$"CZTJ3/"BMTPMFEUPSFEVDFE. TVCHSPVQTDBOQBSUJBMMZFYQMBJOUIFJSNPSQIPMPHJDBMGFBUVSFT JO. UVNPSDFMMJOWBTJPOBOENJHSBUJPO TVHHFTUJOHUIBU1*,$"FY. DMVEJOHUVNPSEJGGFSFOUJBUJPO)PXFWFS UIFQSFDJTFNFDIBOJTN. . QSFTTJPOJTJOWPMWFEJODBODFSDFMMJOWBTJPO *OUIJTTUVEZ XF. JTZFUUPCFEFGJOFE. GPVOEUIBU1*,$"VQSFHVMBUJPOXBTBTTPDJBUFEXJUIUVNPSDFMM. 'FXTUVEJFTIBWFJOWFTUJHBUFEUIFDPSSFMBUJPOCFUXFFO1*,. JOWBTJPO1*,$"FYQSFTTJPOMFWFMXBTBTTPDJBUFEXJUIUVNPS5. $"JNNVOPSFBDUJWJUZBOEQBUJFOUTVSWJWBMJOHBTUSJDDBODFS. TUBHF XIJDISFQSFTFOUTUIFJOWBTJPOEFQUIPGUVNPSDFMMTJOWJT. 4FWFSBMCSFBTUBOEDPMPSFDUBMDBODFSTUVEJFTEFNPOTUSBUFEUIBU. DPVTIPMMPXPSHBOTJODMVEJOHUIFTUPNBDI5IFJOWBTJPOEFQUI. FMFWBUFE1*,$"FYQSFTTJPO BTPCTFSWFEVTJOHJNNVOPIJTUP. PGUVNPSDFMMTDBOCFDBUFHPSJ[FEBTTVQFSGJDJBMJOWBTJPO 5BOE. DIFNJTUSZ XBTDPSSFMBUFEXJUIXPSTF04 "OPUIFSTUVEZVTJOH. 5 BOEEFFQJOWBTJPO 5BOE5 8FPCTFSWFEBTUBUJTUJDBMMZ. BTNBMMDPIPSUPGQSJNBSZHBTUSJDDBODFSDBTFTSFWFBMFEUIBU. TJHOJGJDBOUEJGGFSFODFJO1*,$"FYQSFTTJPOCFUXFFOUIFTFDBU. 1*,$"PWFSFYQSFTTJPOXBTBQSFEJDUJWFNBSLFSGPSNFUBTUB. FHPSJFT 1 'VSUIFSNPSF BOJODSFBTFJOMZNQIBUJDWFTTFM. TJTJOHBTUSJDDBODFSTIPXFWFS TVSWJWBMBOBMZTJTXBTOPUQFS. JOWBTJPOGSFRVFODZXBTPCTFSWFEJOUIF1*,$"QPTJUJWFHSPVQ. GPSNFE8FGPVOEUIBUUIF1*,$"QPTJUJWFHSPVQXBTNPSF. 1 #FDBVTFMZNQIBUJDWFTTFMJOWBTJPODBOJOEJDBUFUVNPS. MJLFMZUPTIPXXPSTF04UIBOUIFOFHBUJWFHSPVQVTJOHBMPH. DFMMJOWBTJWFOFTT UIJTPCTFSWBUJPOBMTPTVQQPSUTUIFIZQPUIFTJT. SBOLUFTUBOEVOJWBSJBUFTVSWJWBMBOBMZTJT 1BOE1 . UIBU1*,$"FYQSFTTJPOJOEVDFTUVNPSJOWBTJWFOFTTJOHBTUSJD. SFTQFDUJWFMZ 5IFTFSFTVMUTTVHHFTUFEUIBUUIFMFWFMPG1*,$". DBODFS5IFSFGPSF PVSSFTVMUTPCUBJOFEVTJOHIVNBODBODFSUJT. FYQSFTTJPODBOSFGMFDUUIFQSPHOPTJTPGHBTUSJDDBODFSQBUJFOUT. TVFTBSFJOBHSFFNFOUXJUIQSFWJPVTJOWJUSPGJOEJOHT. 5PTVNNBSJ[F 1*,$"PWFSFYQSFTTJPOXBTBTTPDJBUFEXJUI. 1*,$"DBOBMTPTFSWFBTBEFUFSNJOBOUGPSUVNPSEJGGFSFO. QPPSTVSWJWBMBOEBHHSFTTJWFDMJOJDPQBUIPMPHJDBMGFBUVSFT TVDI. UJBUJPOPSNPSQIPMPHJDBMQIFOPUZQFT*OBCSFBTUDBODFSTUVEZ . BTEFFQJOWBTJPOPGUIFHBTUSJDXBMM IJHI5TUBHF BOEMZNQIBUJD. JODSFBTFE1*,$"JNNVOPSFBDUJWJUZXBTBTTPDJBUFEXJUIIJHI. JOWBTJPO1*,$"FYQSFTTJPO BTTFTTFECZJNNVOPIJTUPDIFNJT. HSBEFNPSQIPMPHZ BTXFMMBTEJGGFSFOUIJTUPMPHZTVCUZQFT JOWB. USZ XBTPCTFSWFEJOJOUFTUJOBMUZQFBEFOPDBSDJOPNB TVHHFTUJOH. . TJWFEVDUBMDBSDJOPNBWFSTVTPUIFSIJTUPMPHZUZQFT "QSFWJPVT. 1*,$"SPMFBTBEFUFSNJOBOUGPSNPMFDVMBSBOENPSQIPMPHJDBM.

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