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Journ al of the Korean Radiological Society 1995: 33( 1) : 59-65
Comparison of Gadolinium Polylysine and Gadopentetate in Contrast Enhanced MR Imaging of
Myocardiallschemia-Reperfusion in Cats1
Tae-Hwan lim, M.D .' .2, Jung Hee lee, Ph.D.2,
Tae-Keun lee, 8.5.2, Chi Woong Mun, Ph.D.2
Purpose: To assess the signal enhancement by gadolinium-DTPA-polylysine (Gd-polylysine) as compared to gadopentetate (Gd-DTPA) in MR imaging of heart that have undergone ischemia-reperfusion, and toestimatetheextent of myocardial damage covered bythe MR signal enhancement.
Materials and Methods: A series of contrast enhanced cardiac MR images were obtained from 17 cats subjected to a 90 minutes of occlusion of the left anterior descending coronary artery (lAD) followed by a 90 minutes of reperfusion. Time courses of changes in the signal intensity (51) of the ischemic area were measured in Gd-polylysine group (8cats) and Gd - DTPAgroup (9cats). The sizeof MR signal enhanced area was then compared to the sizes of infarction and the area at risk revealed byTTC histochemical staining.
Results: Maximum 515 were obtained at 60 minutes and 30 minutes after injection of the contrast materia l, respectively for Gd-polylysine group and Gd-DTPA group . 5ignal enhancement was stronger and persistent for a longer period in Gd-poly’ysine group than in GD-DTPA group. 5izes of the enhanced area, the infarction , and the area at risk were about 30%, 15%, and 50% of the total left ventricle (l V) area; the difference between the groups was statistically insignificant.
Conclusion: Gd-polylysine can be used better for a blood pool marker than Gd-DTPA in MR imaging of myocardial ischemia, due to its strong and persistent signal enhancement. The MR signal enhanced area includes both the infarcted area and a portion of the area at risk.
IndexWords: Contrast media, experimental studies Gadolinium Myocardium, infarction Magnetic resonance(MR) , contrast enhancement
INTRODUCTION
Various kinds of contrast materials have been employed for MR imaging of myocardial ischemia in research and clinical fields , and shown to have the potential to differentiate ischemic from normal (1-6) , occlusive from reperfused (7 -12), and irreversibly damaged
'Oepartment of Radiology, Asan Medical Center, University ofUl san College of Medicine
20epartment ofR adiological SCiences, Asan Insti tute for Life Sciences This study was supported by a research grant from the Korean Radiological Society provided by SCher ing, Korea ReceivedMay2, 1995 ;AcceptedJune 22, 1995 Address reprint requests to :Tae-Hwan Lim, M.O., Oepartm ent of Radiology, Asan Medical Center, University of Ul san College 이 Medicine 388-1 poong Nap-dong, Song Pa-Ku , SeouI138- 040, Korea. Tel. 82-2- 224-4364,4400 Fax 82-2- 476- 4719
from reversibly damaged myocardium (13 -15). Recently , owing to the advent of the fast MR imaging techniques , first - pass MR imaging of ischemic myocardium is widely used for assessing the status of myocardial perfusion (16 -22). Variation in the signal intensity (81) obtained by the first - pass of a bolus injected contrast material reflects the status of myocardial perfusion of the ischemic zone. However, for a complete evaluation of the myocardial perfusion status, a delayed signal enhancement obtained after saturation of the blood pool by a contrast material should also be assessed (11 , 12, 14)
Among various kinds of contrast materials for MR imaging of myocardium , gadolinium - DTPA-p이ylysine
(Gd - polylysine) has been shown to exhibit a strong and a persistent signal enhancement of the ischemic zone with a delayed time to reach a maximum level of 81 (12)_
m j
Journal of the Korean Radiological Society 1995; 33( 1) : 59-65
Gd-polylysine enhanced MR imaging could be also used 10r differentiation 01 ischemic 1rom normal myocardium , and 1urthermore, 10r determination 01 the degree 01 myocardial damage within the ischemic zone (12, 15). Although the exact mechanism and pathophysiological signi1icance 01the signal enhancement have not yet been clearly de1ined , an increase in the amount 01 water molecule due to hyperemia, interstitial edema, and intracellular edema, and consequently an increase in the amount 01 the con trast material in the ischemic area , is suggested as a possible 1actor 10r evoking the signal enhancement in the MR imaging (11 ’ 15). According to Schumann -Giampieri et al , Gd-polyIysine exhibits a high and delayed relaxivity due to its large molecular size (23). However, it has not been tested whether a small molecular sized contrast material such as Gd -DTPA would exhibit the same time course and the degree 01 the signal enhancement 10r MR imaging 01 the ischemic myocardium. Furthermore , the extent 01 myocardial damage covered by the MR signal enhancement is also important 10r evaluation 01 the isèhemic myocardium. There10re , in ‘ this study, we intended (a) to assess the time course and the degree 01the signal enhancement in Gd-p이ylysine
and Gd-DTPA enhanced MR imagings 01 myocardium and (b) to determine the extent 01 myocardial damage enhanced by contrast enhanced MR imaging.
MATERIAlS and METHODS
Animal Preparation Seventeen adult cats weighing 2.7 to 4.0 Kg (mean
3.3 Kg) were examined in this study. The animals were divided into two groups : in group 1 (n=9) , animals were subjected to Gd -polylysine enhanced MR imaging; in group 2 (n=8) , animals were subjected to GdDTPA enhanced MR imaging.
A detailed procedure 10r the animal preparation in this study was based on the previously published method (12). Each cat was anesthetized by 0.5%-1.0% halothane with an occasional use 010.6 mg/kg 01 pancronium bromide (Panslan; Reyon Pharmaceuti cal , Seoul , Korea) 10r skeletal muscle relaxation. Blood pressure and heart rates were recorded on a cardiac monitor (model 90603A, Space Labs Inc. , Redmond , WA. USA) via a cannula inserted into the 1emoral artery. Femoral venous cannulation was made 10r administration 01 drug and contrast materials. After opening the chest, the left anterior descending coronary artery (LAD) was exposed distal to the 1irst diagonal branch 01 the left main coronary artery. The occluder attached to the end 01 the snare loop was extended to the outside 01 the magnet so that occlusion and reper1usion 01 the LAD were induced simply by 1astening and releasing the occluder without removing the animal 1rom the magnet during the experiment. Obstruction 01 the LAD was con1irmed by observing the
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change in color 01 the myocardium at risk on a preliminary test occl usion.
Contrast Materials Gd -DTPA -polylysine (Gd-polylysine; Schering A
G. , Berlin , Germany; mw=40,000-50,000) and Gadopentetate (Gd -DTPA ; Schering A. G. , Berlin , Germany ; mw=983) were i 미 ected through the 1emoral vein , 0.2 mmoles/kg and 0.1 mmoles/kg , respectively , in Gdpolylysine group and Gd-DTPA group. Relaxivities , acute tolerance levels , and phamarcokinetic properties 01 the two agents were previously studied by Schuhmann - Giampieri et al (23). Gd -polylysine contains 60-70 gadolinium atoms per a p이 ylysine m 이
ecule. The T1 relaxation rates measured 10r Gd-poly-Iysine and Gd -DTPA are 13.1 (mM/L) -1 sec - 1 and 3.7 (mM/L) • 1 sec - 1’ respectively ; and the T2 relaxation rates , 14.3 (mM/L) - 1 sec - 1and 4.1 (mM/L) -1 sec- \ respectively. The hal f-l i1e 01 elimination is 1.9 hr 10r Gd polylysine and 0.6 hr 10r Gd -DTPA (23)
MR Imaging MR imaging was per10rmed on a Bruker Biospec
4.7T Imaging and Spectroscopy System (Bruker, Fä landen , Switzerland) operating atthe'H resonance1requency 01200.14 MHz. Surgically prepared animals attached with an anesthetization device were positioned supine in the center 01 the RF coi l. A stable anesthetization was maintained during the entire experiment course while monitoring blood pressure and pulse rate and per10rming the arterial blood gas analysis. An arterial pulse-gated spin-echo multislice imaging sequence was used to acquire images. AII images were acquired in the transverse axial plane, and 7 slices per a scan were obtained 10r 150 seconds. Images in the sagittal plane were also acquired occasionally to provide an additional con1irmation 01 the signal enhancement 01 the ischemic zone. The 10110wing set 01 acquisition parameters was used: TR (repetition time)=300 msec, TE (echo time)=25 msec, slice thickness=3 mm , inter -slice gap=1.4mm , FOV (1ield 01 view)=10cm , phase encoding steps=128, and NEX (number of excitations)=8.
Cats were subjected to a 90 minutes 01 occlusion 01 the LAD 10110wed by a 90 minutes 01 reperfusion. AII MR imaging experiments were started with acquising 01 baseline images (B L) be10re ligation 01 the LAD. After the ligation (L), MR images were acqu ired at 60 and 90 minutes after the ligation (denoted as L60 and L90, respectively) , with the same imaging parameters as 10r the BL. Reper1usion (R) 01 the LAD was started immedi ately after acquiring the image at L90, then , a series 01 the reper1usion images was obtained during the reperfusion period , 15, 30, 60 and 90 minutes after the reper1usion (denoted as R15, R30, R60 , and R90, respectively) using the same imaging parameters. The contrast materials were injected at the initiation 01
Tae -Hwan Lim, et al: Gadolinium Polylysine and Gadopentetate in Contrast Enhanced MR Imaging of Myocardial Ischemia
reperfusion . moved from the magnet and sacrificed by intravenous
injection of KCI solution . Cardiectomy was performed , Postmortem Histochemical Staining and the aorta was cannulated for infusion of methylene
After MR imaging was finished , the animal was re- blue into the myocardium through the right coronary
MC) 햄MR Lab.효쉰효찮 : a b c Fig . 1 . a. Nonenhanced MR image taken belore the LAD ligation (= BL) b. Gd-polylysine enhanced MR image taken 60 minutes after the LAD reperlusion and contrast injection (=R60). c. Photograph 01 TTC stained cardiac specimen sliced at the same level as the MR images. Ischemic zone shows a very strong signal enhancement (open arrows) at 60 minutes 01 the reperfusion. On the MR image , the size 01 the enhanced area was 32.8 % 01 the total LV area; on the TTC staining , the size 01 the area at risk (asterisks) and that 01 the area 01 inlarction (arrow) were 38.4% and 14.4 % 01 the
totalleft ventricle area, respectively , in this case. LV : left ventricle, RV: right ventricle
쐐MR Lab CHS 27 : 03 a b c Fig. 2. a. Nonenhanced MR image taken 90 minutes alter the LAD ligation (=L90l. Note the thinning 01 the anterior wall 01 left ventricle (arrow)
b. Gd-DTPA enhanced MR imagetaken 30 minutes after the LAD reperlusion and contrast injection (=R30)
c. Photograph 01 TTC stained cardiac specimen sliced atthe same level as the MR images. Ischemiczone can be depicted Irom the normal myocardium at 30 minutes 01 the reperlusion by the signal enhancement (open arrows). On the MR image, the size 01 the enhanced area was 39.6 % 01 the total LV area ; on the TTC staining , the size 01 the area at risk (asterisks) and that 01 the area 01 inlarction (arrow)
were 50.3% and 1 O. 9% 01 the total LV area, respectively , in this case. LV : leftventricl e, RV: rightventricle
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Journal of the Korean Radiological 50ciety 1995 ; 33( 1) : 59-65
5.0
4.5 .., ‘ I ------ Gd.polylysine ;t: . _ 1 ---Q--' Gd-DTPA ifj 4.0'" = @
를 3.5
뜸 3.0 。,
잉 2.5 >
품 2.0 @
c::: 1.5
1.0 BL L60 L90 R15R30 R60 R90
Time (min)
Fig. 3. Tim e courses 01 changes in the signal intensity belore and after injection 01 contrast materials. Contrast materials were injected immediately after the reperfusion 01 the LAD was started. 5ignal enhancement by Gd-polylysine requires a longer time lor reaching the maximum level , exhibits a stronger 51 , and persists lor a longer period than by Gd-DTPA.
mm』m
〉」
‘。-~ )
18 ω
i@>mi
~
60
50
40
30
20
10
0 AR/LV (TTC)
AI/LV (TTC)
뽑 Gd-polylysine m Gd.DTPA
EA/LV (MRI)
Fig. 4. Comparison between the size 01 the enhanced area (EA) shown on MR images and the size 01 the area 01 inlarction (A!l and the area at risk (AR) revealed on TTC stained specimens. The sizes on the ordinate are expressed as a relative value (%)
to the size 01 the totalleftventricle (LV) aréa
artery (RCA) and the LAD proximal to the l igation site. The LAD was also cannulated distal to the ligation site for infusion of 1.5% 2, 3, 5-triphenyltetraz이 ium chloride (TTC) solution into the myocardium at risk. Solutions of methylene blue (20 ml) and TTC (10 ml) were infused simultaneously through the aortic and LAD cannula, respectively , using an injection pump (Harvard Apparatus , Millis , Mass). The stained cardiac specimen was stored in a 10% formalin solution for 12 -16 hours , and the specimen was dissected at the same planes where the MR images were acquired to be viewed for photographing. Photographs of the TTC stained cardiac
specimens were scanned into a Macintosh computer to measure the sizes of the area of infarction , the area at risk , and the area of totalleft ventricle (LV) by using a public domain image processing software (Image 1.35, NIH). The area of infarction was defined as a TTC unstained area (white color) and the area at risk as a TTC stained area (brick-red color). The sizes were measured on a slice of the specimen which was the most closely correlated to the MR image where the Sls were measured.
Quantitative Analysis of MR Images MR images were reviewed by a MR radio logist (T
H. 니. Signal intensities (Sls) were measured on the ischemic myocardium and the back muscle using ASPECT 3000 computer (Bruker , F허landen , Switzerland) ;
’ the Sls were the relative values to those the paraspinal muscle. Regions of interest (ROls) for the SI measurements consisted of 44 pixels. The sizes of the en hanced area and the tota l LV area were measured on an image slice at the mid-ventricular level where the size of the enhanced area was usually the greatest. The sizes of the enhanced area measured relative to the total LV area on the MR images were compared to those of the area of infarction and the area at risk measured relative to the total LV area on the TTC stained specimens. AIi data were expressed as mean (M) i: standard error (S티 of the measurements. Statistical significance of the data was tested with one -way analysis of variance (ANOVA) , paired t and unpaired t tests. P value less than 0.05 was considered statistically significan t.
RESULTS
The two contrast materials showed tnarked differences in the time course and the degree of the signal enhancement in the MR imaging (Fig. 1 & 2). Gd - poly-
‘ Iysine en hanced MR imaging showed a stronger signal enhancement with a slower time to reach the maximum SI than Gd -DTPA: the maximum SI , 4.5 i: 0.4, was obtained at R60 for Gd-polylysine enhancement, whereas the maximum 51 , 3.9 i: 0.6, was obtained at R30 for Gd DTPA enhancement. For Gd - p이ylysine group, the enhanced signal was maintained throughout the 90 minutes of the reperfusion period , however , in Gd - DTPA group, it decreased rapidly after the 30 minutes of the reperfusion period (Fig. 3).
The size of the enhanced area shown on the MR images was larger than that of the area of infarction and smalier than that ofthe area at risk revealed on the TTC stained specimens in both groups. The size of the enhanced area was 31 .3 i: 1.8% and 33.1 i: 2.1 % of the total LV area , respectively for Gd - polylysine and Gd - DTPA enhancements. The sizes of the infarction were 15.2 i: 1.1 % and 14.3 i: 1.1 % of the total LVarea, respectively in Gd -polylysine group and Gd - DTPA group and the sizes of the area at risk were 50.3 i: 3
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Tae-Hwan Lim, et al ‘ Gadolinium Polylysine and Gadopentetate in Contrast Enhanced MR Imaging of Myocardial Ischemia
8% and 48.1 :t 2.0 % of the total LV area, respectively in Gd - p이ylysine group and Gd - DTPA group. There was no difference in the data between the two groups.
DISCUSSION
In this study, we found that Gd - p이ylysine exhibited a stronger, a persistent, and a delayed signal enhancement of the ischemic zone than Gd - DTPA. The pattern of the signal enhancement achieved by GD - polylysine may be attributed to the biophysical property of the contrast material. Gd - p이ylysine is a relatively high molecular weighted Gd - DTPA derivatized polymer (mw=40-50 kd ; DP=230 by LALLS). When the cationic p이ymer p이ylysine is substituted with the Gd -DTPA derivative, the molecule loses its positive charge and displays an excellent tolerance profile. The LDso in mice is 17 mmol Gd/kg which is significantly higher than Gd -DTPA. In addition to its excellent tolerance profile , its high molecular weight results in the plasma relaxivity of about 14 Lmmol - 1s - 1 at 4.7 Tesla magnet, which is 3-4 times higher than that of Gd -DTPA. The hal f-l ife of elimination is also 3-4 times longer for Gd polylysine (1 .9 hr) than for Gd -DTPA (0.6 hr) (23 , 24). Effects of the strong relaxivity and the long hal f-l ife of Gd - p이ylysine on the MR signal enhancement were well demonstrated in this study.
Pathophysiologic significance ofthe signal enhancement in myocardium under ischemia and reperfusion can be generally explained by foliowing three aspects First, reactive hyperemia occurring after ischemia and reperfusion of myocardium should play a role in increasing the amount of blood flow and the amount of the contrast material in the ischemic zone. Second, intracellular edema, destruction of the cell membrane, and a loss of the compartmentalization in the damaged myocardium can accumulate more water molecules and contrast material in the ischemic zone. Third , extravasation of the contrast material due to leaky capillary can also play an important role for the signal enhancement (25). From the observation in this study that it took a lon'ger time for 'Gd-polylysine enhancement to reach the maximum SI and that the enhanced signal persisted a longer period , one can speculate that extravasation into the interstitial space and clearance from the interstitial space were delayed because of the macromolecular property of Gd-polylysine. The signal enhancement was stronger in Gd-p이ylysine group than in Gd -DTPA group resulting in a better delineation of the enhanced area in Gd - polylysine group Exact mechanism of the stronger signal intensity achieved by Gd-polylysine is still not well understood, however, it
can be better used than Gd-DTPA as a blood pool marker in the MR imaging of myocardial ischemia. One drawback of Gd ← p이ylysine is that it requires a long waiting time until the maximum signal enhancement is achieved (60 minutes after the contrast material i 미 ection).
The size of the enhanced area on the MR images was larger than that of the area of infarction and smaller than that of the area at risk on the TTC stained specimens. The pathophysiological significance of this fact can be interpreted in two ways. First, the enhanced area on MR imaging includes both the area of infarction and a portion of the area at risk. The portion ofthe area at risk included in the enhanced area is usually the area of hyperemia or interstitial edema located near peripheral to the infarcted zone. Second, the far peripheral portion of the area at risk which appears normal on the MR images may be an area of myocardium that was salvaged by collateral blood flows drawn from the outside of the area at risk during the ischemic period. No significant difference was observed in the sizes of the enhanced area between the two groups in this study , implying that the ultimate distribution of the contrast material in the ischemic myocardium after saturation of the contrast material in the blood pool (steady -state) is independent of the size ofthe contrast material.
In conclusion , by comparing Gd - polylysine with Gd DTPA as a paramagnetic contrast agent for MR imaging of the ischemic myocardium in cats , we found that Gd - polylysine can be better used as a blood pool marker because of its strong and a persistent signal enhancement of the ischem ic zone. The en hanced area includes the area of infarction and a portion of the area at risk surrounding the area of infarction.
Acknowledgments The authors express their sincere thanks to Dr.
Weinmann and Dr. Muhler at Shering A. G. Berlin , Germany for providing the Gd-DTPA-polylysine. The authors also thank many physicians at the Asan Medical Center , especially Dr. Pyung Hwan Park for lending his expertise for anesthetization , Dr. Dong - Man Seo for cardiac surgery, Dr. Seung Wook Park and Dr. Young Cheoul Doo for helpful discussions on general cardiology.
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Tae - Hwan Lim, et al: Gadolinium Polylysine and Gadopentetate in Contrast Enhanced MR Imaging of Myocardial Ischemia
대 한 방 사 선 의 학 회 지 1995; 33( 1) : 59-65
심근허혈 -재관류 손상에서 가돌리니움-폴리라이신과 가도펜테테이트를 이용한 조영증강 자기공명영상의 비교:
고양이에서의 설험적 연구1
1 울산대학교 의과대학 진 단방사선과학교실
2아산생명과학언구소 방사선의학연구과
임태환1 , 2 • 이정희2. 01대근2 • 문치웅2
목 적:첫째, 허혈-재관류 손상을 입은 심근의 자기공명영상 (MRI)에서 가돌리니움-폴리라이신 ( Gd-polylysine)과 가
도펜테테이트 (Gd - DTPA)의 조영증강 효과의 차이를 비교하고 , 둘째, MRI상 나타나는 조영증강 부위와 2, 3, 5-triphenyl
tetraz이ium chloride (πc) 염색상 나타나는 심근 손상 부위의 상호 연관성을 밝힌다.
대상 및 방법 :17 마리의 고앙이에서 관상동맥 좌전행지 (LAD)를 90 분간 결찰하고 90 분간 재관류하는 동안 MRI를 추적
검사하였다. 이중 8 마리에서는 조영제로 Gd-polylysine을 주사하였고 9 마리에서는 Gd - DTPA를 주사하였다. 심근허혈 -재
관류 손상이 일어난 것으로 추정되는 조영증강 부위에서 MRI 신호강도를 측정하여 허혈과 재관류의 시간에 따른 변화를
Gd-polylysine군과 Gd - DTPA군 간에 비교하였다. 또한, MRI상의 신호증강 부위의 크기와 nc 염색상의 경색 부위 및 경색 위 험 부위의 크기를 측정하고 전체 좌심실 면적의 크기에 대한 비율로 나타내어 비교하였다.
결 과 :MRI상 허혈-재관류 손상을 받은 심근 부위는 조영증강이 되었으며, Gd-polylysine군은조영제 주입 후 60 분에,
Gd-DTPA군은 조영제 주입 후 30 분에 각각 최대 신호강도를 보였다. Gd-polylysine은 보다 길고 강한 조영증강 효과를 나타
내었다. MRI상의 조영증강 부위는 전체 좌심실의 30%였으며, nc 염색상의 경색 부위와 경색 위험 부위는 각각 전체 좌심실
의 15%와 50%였다. Gd-polylysine군과 Gd-DTPA군 사이에 조영증강 부위, 경색 부위, 경색 위힘 부위의 차이는 없었다.
결 론: Gd -polylysine은 심근경색-허혈 손상의 MRI에 적함한 조영제로 생각되고, MRI상의 조영증감 부위는 nc상의 경
색 부위 전체와 그 주변의 경색 위럼 부위 일부를 포함하는 것으로 보인다.
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일 시 : 1995년 11월 4일(토)-5일(일)
장 소: 삼성의료원대강당
등 록 비 : 사전등록 현장등록
전 문의 40,000원 50,000원
전 공의 20,000원 30,000원
사전등록 마감 : 1995년 10월 20일(금)까지
연사및언제 PETER C BUETOW, M.D. Chief, Gastrointestinal Radiology Department of Radiologic Pathology Armed Forces Institute of Pathology , Washington , D.C.
1. Colorectal Carcinoma 2. Pediatric Li ver Tumors 3. Tumors of the Pancreas Part I 4. Tumors of the Pancreas Part 11
MARC S, LEVINE, M.D. Distinguished Scientist Department of Radiologic Pathology Armed Forces Institute of Pathology, Washington , D.C .
1. A Pattern Approach to the Esophagus 2. Update on Peptic Ulcer Disease 3. Radiology of Metastatic Disease to the GI Tract 4. The Ins and Outs of Abdominal Gas
MARK J. KRANSDORF, M.D. Clinical Associate Professor of Radiology Department of Radiology University of Virginia , Charlottesville, VA
1. Juxta - articular Lesions I 2. Juxta -articulat Lesions 11 3. Common Fibrous Lesions of Bone 4. Common Osseous Lesions of Bone
--- --- -- ------- 절 취 선 ----- --- -- --- - --
사전등록양식
λcl p킥 전문의( 전공의(
À- ι← • J- 극 •
송 금 처 : 평화은행 025 -01 -0001 -037 (대한방사션의학회 서정호) 사전등록처 : 본학회 사무국 (TEL 578-8003, FAX 529-7113)
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