ÐÏࡱá > þÿ ò ô þÿÿÿ ð ñ ÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿì¥Á '` ø¿ ås bjbj{P{P .œ : : /j % ÿÿ ÿÿ ÿÿ ¤ . . . . . . . B Š Š Š 8  „ F B n  n ¶ $ " F F F z z z Õ × × × × × × $ þ h f ¦ û - . û z z û û û . . F F 4 ( ¿ ¿ ¿ û œ . F . F + ª ¿ û Õ ¿ ¿ . . ¿ F b `äX¿ÔÊ Š — p ¿ > 0 n ¿ T ¿ . ¿ X z Ž ¿ œ ¨ S z z z û û [ d z z z n û û û û B B B $ f $ B B B f B B B . . . . . . ÿÿÿÿ Supplementary Materials Molecular Progression of Squamous Cell Carcinoma of Head and Neck (SCCHN) SCCHN occurs as a consequence of the accumulation of genetic and epigenetic changes resulting from exposures to various carcinogens, such as tobacco, alcohol, betel quid chewing, and marijuana use ADDIN EN.CITE ADDIN EN.CITE.DATA (1-3). In 1953, Slaughter et al. coined the concept of “field cancerization” to describe the finding that grossly normal appearing epithelial tissue adjacent to an oral cancer, when examined under a microscope, contained multiple foci of oral premalignant lesions (OPLs) and malignant lesions ADDIN EN.CITE Slaughter1953145(4)14514517Slaughter, D. P.Southwick, H. W.Smejkal, W.CancerCancer963-8651953/09/01*Carcinoma, Squamous Cell*Mouth Neoplasms1953Sep0008-543X (Print)13094644http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=13094644eng(4). This concept implies that the exposure to carcinogens affects the entire aerodigestive tract, giving rise to multiple foci of carcinogenesis. This theory began to be elucidated by Califano and his colleagues, who explored the molecular basis for this concept in SCCHN carcinogenesis ADDIN EN.CITE Califano19962513(5)2513251317Califano, J.van der Riet, P.Westra, W.Nawroz, H.Clayman, G.Piantadosi, S.Corio, R.Lee, D.Greenberg, B.Koch, W.Sidransky, D.Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Hospital, Baltimore, Maryland 21205-2195, USA.Cancer ResCancer Res2488-9256111996/06/01Carcinoma, Squamous Cell/*genetics/pathologyChromosomes, Human, Pair 9Clone CellsGenetic MarkersHead and Neck Neoplasms/*genetics/pathologyHeterozygoteHumansMicrosatellite RepeatsPrecancerous Conditions/*genetics/pathologySequence Deletion1996Jun 10008-5472 (Print) 0008-5472 (Linking)8653682http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8653682eng(5). As described in Figure 1 (original text), SCCHN evolves through several phenotypic changes from normal mucosa to hyperplasia, dysplasia, carcinoma in situ, and invasive carcinoma. These phenotypic changes take place as the allelic imbalances accumulate, including loss of heterozygosities (LOH) at 3p, 9p and 17p, resulting in inactivation of tumor suppressor genes, such as p53, p16 and fragile histidine triad (FHIT), and amplification of oncogenes, such as cyclin D1 on 11q13 ADDIN EN.CITE ADDIN EN.CITE.DATA (5-7). Studies have shown a correlation between the accumulation of genetic imbalances at these chromosomal loci with histopathologic progression of premalignant lesions ADDIN EN.CITE ADDIN EN.CITE.DATA (5-7). These biomarkers can therefore serve as molecular targets for chemoprevention and for risk-stratification. Recent chemoprevention clinical trials have started to use biomarkers such as cyclin D1 and p16 as surrogate markers for treatment response and to identify a high risk population ADDIN EN.CITE ADDIN EN.CITE.DATA (8, 9). History of SCCHN Chemoprevention The idea of using dietary supplements to inhibit carcinogenesis dates back to the 1920s and 1930s, when Wolbach and Howe reported the relationship between vitamin A deprivation and risk of carcinogenesis in the rat, and reversal of premalignant lesions by dietary restoration of vitamin A ADDIN EN.CITE ADDIN EN.CITE.DATA (10, 11). In 1929, Berenblum reported inhibition of tar painting-induced skin tumors in rats by painting the exposed areas with a dilute solution of mustard gas ADDIN EN.CITE Wattenberg19662178(12)2178217817Wattenberg, L. W.Cancer ResCancer Res1520-62671966/07/01Neoplasms, Experimental/*chemically induced/*prevention & control1966Jul0008-5472 (Print)5330111http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5330111eng(12). Conney et al. in the 1950s, studied the “metabolism of carcinogens” by induction of enzyme synthesis by 3-methylcholanthrene as a way to prevent cancer ADDIN EN.CITE Conney19568475(13)8475847517Conney, A. H.Miller, E. C.Miller, J. A.Cancer ResCancer Res450-91651956/06/01*Benzene DerivativesColoring Agents/*metabolismLiver/*drug effects1956Jun0008-5472 (Print) 0008-5472 (Linking)13330038http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=13330038eng(13). In 1965, Wattenberg first used the term “chemoprophylaxis” to describe the administration of chemicals to inhibit the progression of preneoplastic lesions ADDIN EN.CITE Wattenberg19662178(12)2178217817Wattenberg, L. W.Cancer ResCancer Res1520-62671966/07/01Neoplasms, Experimental/*chemically induced/*prevention & control1966Jul0008-5472 (Print)5330111http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=5330111eng(12). In 1976, Michael Sporn introduced synthetic vitamin A analog as a potential agent to prevent carcinogenesis and coined the term chemoprevention, which he defined as the administration of natural or synthetic compounds to reverse, suppress, or prevent the development of cancer ADDIN EN.CITE ADDIN EN.CITE.DATA (14, 15). The first chemoprevention clinical trial was reported in 1986 by Hong and colleagues, demonstrating the reversal of, and reduction in the size of, OPLs by high dose 13-cis retinoic acids (13-cRA) at 50-100 mg/m2 a day ADDIN EN.CITE Hong1986390(16)39039017Hong, W. K.Endicott, J.Itri, L. M.Doos, W.Batsakis, J. G.Bell, R.Fofonoff, S.Byers, R.Atkinson, E. N.Vaughan, C.et al.,N Engl J MedN Engl J Med1501-5315241986/12/11AgedClinical Trials as TopicFemaleHumansIsotretinoinLeukoplakia, Oral/*drug therapy/pathologyMaleMiddle AgedRandom AllocationTretinoin/administration & dosage/adverse effects/*therapeutic use1986Dec 110028-4793 (Print)3537787http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3537787eng(16). High dose 13-cRA was also found to be effective for prevention of second primary tumor (SPT) in SCCHN patients ADDIN EN.CITE ADDIN EN.CITE.DATA (17). However, the challenges were significant toxicities, recurrence of oral leukoplakia on discontinuation of 13cRA, and loss of benefits at long-term follow-up ADDIN EN.CITE ADDIN EN.CITE.DATA (16, 18). Subsequently, several other studies were designed to mitigate these challenges. Lippman et al. designed a study using high dose (1.5mg/kg/day) 13-cRA for 3 months for induction followed by low dose (0.5mg/kg a day) maintenance for 9 months ADDIN EN.CITE ADDIN EN.CITE.DATA (19), but failed to demonstrate an effect at long-term follow-up ADDIN EN.CITE Papadimitrakopoulou19971349(20)1349134917Papadimitrakopoulou, V. A.Hong, W. K.Lee, J. S.Martin, J. W.Lee, J. J.Batsakis, J. G.Lippman, S. M.Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4096, USA.J Natl Cancer InstJ Natl Cancer Inst257-88931997/02/05Anticarcinogenic Agents/pharmacology/*therapeutic useCarcinoma, Squamous Cell/*drug therapy/*prevention & controlCell Transformation, Neoplastic/drug effectsFollow-Up StudiesHead and Neck Neoplasms/prevention & controlHumansIsotretinoin/pharmacology/*therapeutic useMouth Neoplasms/*drug therapy/*prevention & controlTime FactorsTreatment Outcomebeta Carotene/pharmacology/*therapeutic use1997Feb 50027-8874 (Print)9017007http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9017007eng(20). Papadimitrakopoulou et al. designed a novel combination regimen consisting of 13-cRA, að- t o c o p h e r o l a n d i n t e r f e r o n ( I F N ) - a l f a A D D I N E N . C I T E A D D I N E N . C I T E . D A T A ( 2 1 ) t o i n d u c e s y n e r g i s t i c e f f e c t s A D D I N E N . C I T E A D D I N E N . C I T E . D A T A ( 2 2 - 2 5 ) a n d t o a t t e n u a t e i s o t r e t i n o i n t o x i c i t y , a n d s h o w e d m o d e s t r e s p o n s e r a t e s o f 5 7 % a t 6 m o n t h s and 48% at 12 months for the treatment of OPL ADDIN EN.CITE ADDIN EN.CITE.DATA (21). Shin et al. used the same regimen for SPT prevention and demonstrated significant reduction in SPT in long-term follow-up of 49.4 months ADDIN EN.CITE ADDIN EN.CITE.DATA (26, 27). Only 1 out of 45 patients developed acute promyelocytic leukemia and no aerodigestive SPT was observed ADDIN EN.CITE ADDIN EN.CITE.DATA (26, 27). However, these were single-arm studies and needed validation in larger randomized trials. Unfortunately, the phase III, randomized trial had to be halted due to poor patient accrual. Furthermore, two other retinoid studies from Europe showed conflicting results. While Pastorino et al. reported that high dose retinol palmitate at 300,000 IU daily for 12 months was effective in reducing SPT incidence in patients with resected stage I non-small lung cancer (NSCLC) ADDIN EN.CITE ADDIN EN.CITE.DATA (28), Bolla et al. reported that etretinate 50 mg a day for 1 month followed by 25mg a day for the following 23 months was not effective in reducing SPT in curatively treated early stage SCCHN patients ADDIN EN.CITE Bolla199413323(29)133231332317Bolla, M.Lefur, R.Ton Van, J.Domenge, C.Badet, J. M.Koskas, Y.Laplanche, A.Department of Radiation Oncology, Universite Joseph Fourier, Centre Hospitalo-Universitaire Albert Michallon, Grenoble, France.Eur J CancerEur J Cancer767-7230A61994/01/01AdultAgedCarcinoma, Squamous Cell/*mortality/therapyDouble-Blind MethodEtretinate/adverse effects/*therapeutic useFemaleHumansMaleMiddle AgedMouth Neoplasms/*mortality/therapyNeoplasms, Second Primary/*prevention & controlOropharyngeal Neoplasms/*mortality/therapyPatient ComplianceProspective Studies19940959-8049 (Print) 0959-8049 (Linking)7917535http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7917535eng(29). Finally, Khuri et al. reported in a larger phase III, placebo-controlled, double-blind trial for early stage SCCHN patients, that low dose isotretinoin, 30mg a day, was not effective in reducing the rates of SPT, death or smoking-related disease ADDIN EN.CITE ADDIN EN.CITE.DATA (30). A recent study also failed to establish a role for low dose 13-cRA, beta-carotene plus retinyl palmitate or retinyl palmitate alone for chemoprevention of oral cancers ADDIN EN.CITE ADDIN EN.CITE.DATA (31). Although these studies were not translated into clinical practice, they led the field of chemoprevention into mainstream cancer research. An ideal chemopreventive agent should be effective and safe in long-term use. There are several natural and synthetic compounds that have been tested for chemoprevention ADDIN EN.CITE Amin2009879(32)87987917Amin, A. R.Kucuk, O.Khuri, F. R.Shin, D. M.Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.J Clin OncolJ Clin Oncol2712-2527162009/05/06AnimalsAnticarcinogenic Agents/isolation & purification/*therapeutic useBiological Products/isolation & purification/*therapeutic useBody Weight*Diet/adverse effects*Dietary SupplementsExercise*Fruit/chemistryHumansNeoplasms/etiology/metabolism/mortality/*prevention & controlRisk Assessment*Risk Reduction BehaviorSignal Transduction/drug effects*Vegetables/chemistry2009Jun 11527-7755 (Electronic)19414669http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=194146692690394JCO.2008.20.6235 [pii] 10.1200/JCO.2008.20.6235eng(32). Among these, GTPs, specifically EGCG, hold strong promise for chemoprevention. EGCG has drawn much attention because of its ubiquity, safety, and most remarkably, its ability to intervene in key molecular signaling pathways involved in tumorigenesis. Moreover, EGCG has shown synergistic interactions with many other chemopreventive and chemotherapeutic drugs in preclinical cell culture and animal model studies. The rest of this paper will focus on the background of EGCG, the preclinical and clinical trials and future directions with emphasis on its synergy with other compounds. References for Supplementary Materials ADDIN EN.REFLIST 1. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993; 328:184-94. 2. Mao L, Oh Y. Does marijuana or crack cocaine cause cancer? J Natl Cancer Inst 1998; 90:1182-4. 3. Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell 2004; 5:311-6. 4. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6:963-8. 5. Califano J, van der Riet P, Westra W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996; 56:2488-92. 6. Mao L, Lee JS, Fan YH, et al. Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nat Med 1996; 2:682-5. 7. Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000; 6:357-62. 8. Lippman SM, Lee JJ. Reducing the "risk" of chemoprevention: defining and targeting high risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture. Cancer Res 2006; 66:2893-903. 9. Tsao AS, Liu D, Martin J, et al. Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila Pa) 2009; 2:931-41. 10. Wolbach SB, Howe PR. Tissue Changes Following Deprivation of Fat-Soluble a Vitamin. J Exp Med 1925; 42:753-77. 11. Wolbach SB, Howe PR. Epithelial Repair in Recovery from Vitamin a Deficiency : An Experimental Study. J Exp Med 1933; 57:511-26. 12. Wattenberg LW. Chemoprophylaxis of carcinogenesis: a review. Cancer Res 1966; 26:1520-6. 13. Conney AH, Miller EC, Miller JA. The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res 1956; 16:450-9. 14. Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer research 1976; 36:2699-702. 15. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Federation proceedings 1976; 35:1332-8. 16. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986; 315:1501-5. 17. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990; 323:795-801. 18. Benner SE, Pajak TF, Lippman SM, Earley C, Hong WK. Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: long-term follow-up. J Natl Cancer Inst 1994; 86:140-1. 19. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoin with beta carotene to prevent oral carcinogenesis. N Engl J Med 1993; 328:15-20. 20. Papadimitrakopoulou VA, Hong WK, Lee JS, et al. Low-dose isotretinoin versus beta-carotene to prevent oral carcinogenesis: long-term follow-up. J Natl Cancer Inst 1997; 89:257-8. 21. Papadimitrakopoulou VA, Clayman GL, Shin DM, et al. Biochemoprevention for dysplastic lesions of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg 1999; 125:1083-9. 22. Calhoun KH, Stanley D, Stiernberg CM, Ahmed AE. Vitamins A and E do protect against oral carcinoma. Arch Otolaryngol Head Neck Surg 1989; 115:484-8. 23. Besa EC, Abrahm JL, Bartholomew MJ, Hyzinski M, Nowell PC. Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol. Am J Med 1990; 89:739-47. 24. Kolla V, Lindner DJ, Xiao W, Borden EC, Kalvakolanu DV. Modulation of interferon (IFN)-inducible gene expression by retinoic acid. Up-regulation of STAT1 protein in IFN-unresponsive cells. J Biol Chem 1996; 271:10508-14. 25. Moore DM, Kalvakolanu DV, Lippman SM, et al. Retinoic acid and interferon in human cancer: mechanistic and clinical studies. Semin Hematol 1994; 31:31-7. 26. Shin DM, Khuri FR, Murphy B, et al. Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial. J Clin Oncol 2001; 19:3010-7. 27. Seixas-Silva JA, Jr., Richards T, Khuri FR, et al. Phase 2 bioadjuvant study of interferon alfa-2a, isotretinoin, and vitamin E in locally advanced squamous cell carcinoma of the head and neck: long-term follow-up. Arch Otolaryngol Head Neck Surg 2005; 131:304-7. 28. Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993; 11:1216-22. 29. Bolla M, Lefur R, Ton Van J, et al. Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study. Eur J Cancer 1994; 30A:767-72. 30. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 2006; 98:441-50. 31. Papadimitrakopoulou VA, Lee JJ, William WN, Jr., et al. Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 2009; 27:599-604. 32. Amin AR, Kucuk O, Khuri FR, Shin DM. Perspectives for cancer prevention with natural compounds. J Clin Oncol 2009; 27:2712-25. PAGE PAGE 6 2 4 5 \ ` a b Å ' ( 7 8 L M N O T U V ôåѾ­¾Ñ¾Ñš‹xl\lI\x8x‹ !hÂj³ CJ OJ QJ aJ mH nH u%j hÂj³ CJ OJ QJ UaJ j hÂj³ CJ OJ QJ UaJ hÂj³ CJ OJ QJ aJ %j h*8 hðoÑ CJ OJ QJ UaJ h*8 hðoÑ CJ OJ QJ aJ $h*8 hðoÑ CJ OJ QJ aJ nHtH !hg3— 5CJ OJ QJ aJ nHtH$hµ-) 5CJ OJ QJ aJ nHo(tH 'h*8 hðoÑ 5CJ OJ QJ aJ nHtHh~m h~m CJ OJ QJ aJ h~m CJ OJ QJ aJ b / P ±. oR ò] ó] ^ ˜^ ú^ __ ` °` qa b Îb –c d Žd ëd ©e ð ð Ý ð Ý Ý Ê È È ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ¾ dð ¤ gdÂj³ $ Æ Ð dà ¤àYDÈ a$gdðoÑ $„Ðdà ¤àYDÈ `„Ða$gdðoÑ $dà ¤àYDÈ a$gdðoÑ ¿s äs ýý V j q u v 8 9 < = > ? Z [ ö ÷ ú û ü íÙíÁ±Á›ÁˆqíZJZ7Zí %hÂj³ CJ OJ QJ aJ mH nH tHuhÂj³ CJ OJ QJ aJ nHtH -j h*8 hðoÑ CJ OJ QJ UaJ nHtH-h*8 hðoÑ B*CJ OJ QJ aJ nHph tH%h*8 hðoÑ B*CJ OJ QJ aJ ph *hÂj³ B*CJ OJ QJ aJ mH nH ph u hÂj³ B*CJ OJ QJ aJ ph .j h*8 hðoÑ B*CJ OJ QJ UaJ ph 'h*8 hðoÑ 6CJ OJ QJ aJ nHtH$h*8 hðoÑ CJ OJ QJ aJ nHtHü ý % &  — ™ ¡ ¢ Ü Ý ì í 8 9 E F ¯ ° ¿ À Ô óàÐàÁ±ÁàÁàž’‚’o‚ž^žàÐàNàž’‚’ hðoÑ CJ OJ QJ aJ nHtH !hÂj³ CJ OJ QJ aJ mH nH u%j hÂj³ CJ OJ QJ UaJ j hÂj³ CJ OJ QJ UaJ hÂj³ CJ OJ QJ aJ %j h*8 hðoÑ CJ OJ QJ UaJ h*8 hðoÑ 6CJ OJ QJ aJ h*8 hðoÑ CJ OJ QJ aJ h\