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(Hypertension. 1996;27:371-376.)
© 1996 American Heart Association, Inc.

Articles

Effects of Cilazapril on Vascular Structure and Function in Essential Hypertension

Wolfgang Kiowski; Lilly Linder; Reto Nuesch; Benedikt Martina

From the Division of Cardiology (W.K., L.L.) and Medical Policlinic (R.N., B.M.), Department of Medicine, University Hospital; Basel, Switzerland.

Correspondence to Prof W. Kiowski, MD, Division of Cardiology, Department of Medicine, University Hospital, CH 8091 Zürich, Switzerland.

	Abstract

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Abstract Hypertension is associated with an altered design of resistance vessels and decreased endothelium-dependent vasodilator response to acetylcholine. A role of angiotensin II in both defects is suggested by animal experiments in which angiotensin-converting enzyme inhibition reverted structural and functional changes. We investigated the effects of 20 weeks of therapy with the angiotensin-converting enzyme inhibitor cilazapril (5 mg twice daily) on the endothelium-dependent response to brachial artery infusions of acetylcholine and the endothelium-independent vascular relaxation after sodium nitroprusside in 22 subjects with mild to moderate essential hypertension. In addition, we measured minimal forearm vascular resistance (ratio of mean arterial pressure and forearm blood flow after heating, ischemia, and ischemic exercise) as an indirect estimate of vascular structure. Cilazapril decreased blood pressure (151±14/99±7 mm Hg during placebo to 138±17/89±8 mm Hg after cilazapril treatment, P<.01) and baseline (42.2±12.6 to 37.1±10.6 U, P<.05) and minimal (3.0±1.1 to 2.4±0.7 U, 15.9±20.2%; P<.05) forearm vascular resistances. The change in minimal forearm vascular resistance was unrelated to age, duration of hypertension, or changes in blood pressure. Sodium nitroprusside increased forearm blood flow from 2.6±1.0 to 11.4±5.9 mL/min per 100 mL and acetylcholine to 21.5±17.8. Both responses did not change after cilazapril. The data provide indirect evidence that cilazapril therapy may improve vascular structure in human hypertension. The lack of relationship between vascular and blood pressure changes would be compatible with experimental evidence supporting a role for angiotensin II in the development and regression of vascular changes, but this needs further study. Therapy with cilazapril for 20 weeks, like other antihypertensive therapy, does not seem to influence endothelial vasodilator function in humans to a significant degree.

Key Words: acetylcholine • angiotensin-converting enzyme inhibitors • blood vessels • hypertension, essential • vascular resistance • vasodilation • endothelium

	Introduction

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Since the description by Furchgott and Zawadzki¹ that the endothelium is obligatory for the vasodilator effects of acetylcholine, it has been increasingly recognized that the endothelium not only separates blood from underlying vascular muscle and preserves blood fluidity but is also important in the regulation of vascular tone by synthesizing and releasing highly potent, vasoactive compounds.^{2 3} The mechanism responsible for the vasodilator effect of acetylcholine has been mostly clarified and can be attributed to endothelial generation of nitric oxide or a substance that spontaneously generates nitric oxide from L-arginine.⁴ Moreover, it has become clear that basal release of nitric oxide in both experimental animals⁵ and humans^{6 7} is involved in the regulation of vascular tone. In addition, the endothelium appears to play a crucial role in the early phases of the development of atherosclerosis,⁸ and alterations of endothelial function and morphology seem to coincide in animals.⁹ Interestingly, arterial hypertension as a key risk factor for the development of atherosclerosis¹⁰ is associated in some^{11 12 13} but not all¹⁴ patients with a decreased vasodilator response of forearm resistance vessels to acetylcholine and a diminished basal release of nitric oxide.^{15 16}

Hypertension also leads to media hypertrophy of the arterioles, resulting in an increased wall-to-lumen ratio,¹⁷ and this alteration could be the ultimate structural factor behind the maintenance and progression of hypertension independent of the initiating factor. A growing body of evidence suggests that autocrine-paracrine vasoactive substances and growth factors are important in modulating vascular structure in hypertension and that the renin-angiotensin system may play a crucial role in this response.^{18 19}

Experimental evidence indicates that ACE inhibition may specifically improve endothelium-dependent vasodilator function in spontaneously hypertensive rats²⁰ and improve vascular structure in animals^{20 21} and humans²² in vitro. Although ACE inhibition with captopril, but not nifedipine, in humans acutely improved the endothelium-dependent vascular relaxation to acetylcholine,¹³ chronic therapy with a variety of drugs or combinations failed to do so despite good BP control.²³ Interestingly, neither captopril nor enalapril improved endothelium-dependent vasodilation in human hypertension,²⁴ but patients were treated for only 7 to 8 weeks. To delineate further the importance of ACE inhibition and BP reduction for endothelium-dependent vascular relaxation, we investigated the effects of more prolonged, ie, 20 weeks, cilazapril therapy in subjects with essential hypertension. In addition, we assessed the effects of therapy on minimal FVR as an indirect measure of vascular structure.^{17 25}

	Methods

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Twenty-two subjects with a history of mild to moderate hypertension (16 men, 6 women) consented to participate in the study (Table), which was approved by the hospital ethics committee. Secondary forms of hypertension were ruled out by a standard medical workup. Ten subjects had never received antihypertensive therapy, and none had been treated with calcium channel blockers or ACE inhibitors in the preceding 3 months.

View this table: [in this window] [in a new window]   Table 1. Demographic Data of Study Population

Study Design
The study was a single-blind study lasting 24 weeks. All previous medication was discontinued, and subjects were given placebo tablets identical in appearance to the active compound. Clinic visits were always in the morning, and subjects were instructed not to take their morning dose on those days. When casual diastolic BP was greater than 95 mm Hg after 3 weeks of placebo once daily, the investigations of endothelial function and vascular structure were scheduled 7 days later with the subject still taking placebo. After the first hemodynamic study, subjects were given 5 mg cilazapril once daily for 1 week. After ensuring that no adverse clinical or biochemical effects had occurred and under the assumption that suppression of Ang II should be as complete as possible, the dose was increased to 5 mg twice daily for the remainder of the 20-week active treatment period irrespective of BP responses. Additional clinic visits were scheduled after 4, 8, and 12 weeks and at the end of the last week of the study period, when the hemodynamic study was repeated. Compliance was assessed by counting the number of returned tablets and was assumed to be good when the number of tablets taken was within 20% of the theoretical value for the respective treatment interval. No dietary instructions were given.

Measurements
During clinic visits, casual sitting BP was assessed with a standard mercury sphygmomanometer, and heart rate was counted from the radial pulse.

Hemodynamic studies were performed in the morning with the subjects recumbent and comfortably resting after a light breakfast in a quiet, air-conditioned room at an ambient temperature of 20°C to 22°C. Under local anesthesia (1% lidocaine), an 18-gauge catheter (Abbocath-T, Abbott) was inserted into the left brachial artery for regional drug infusion and recording of arterial pressure with a Statham P23 Pb pressure transducer. Heart rate was calculated from the continuously recorded electrocardiogram.

FBF was measured bilaterally by venous-occlusion plethysmography⁷ with the hands excluded from the circulation by inflating pediatric BP cuffs placed around the wrists to 50 mm Hg above systolic pressure 1 minute before and during measurements. Infusion experiments were done on the left forearm, and blood flow measurements on the right arm served as continuous control. Assessment of minimal FVR was performed on the right, noncannulated arm.

Determinations of FBF were made by analyzing four to six consecutive recordings (three to four for calculation of minimal FVR) with a digitizing board and suitably programmed computer. The mean value was taken for statistical evaluation. FVR was calculated by dividing mean arterial pressure by FBF and is expressed as arbitrary units.

ACE Inhibition by Cilazapril and Minimal FVR
Subjects were allowed to rest for 30 minutes after completion of instrumentation until basal FBF, intra-arterial BP, and heart rate were recorded. Next, the right arm was wrapped in a heating blanket, and subjects were thickly covered with blankets to induce profuse sweating. After 20 minutes, the blankets were removed and the BP cuff of the plethysmograph on the noncannulated arm was inflated to a pressure at least 30 mm Hg above intra-arterially measured systolic pressure. The subjects were instructed beforehand that this may become painful and that they were expected to endure the ischemia as long as possible. When the subjects volunteered that they might not tolerate the ischemia much longer, they were asked to do handgrip exercise (without load) for 1 minute. When the subjects stopped exercising, the upper arm cuff was released and FBF was measured four to six times every 10 to 15 seconds. Intra-arterial BP was monitored simultaneously in the opposite arm. The time of forearm ischemia until the beginning of exercise and exercise duration were noted during the placebo investigation for each subject, and identical timing was used during the second investigation at the end of the 20-week treatment period.

ACE Inhibition by Cilazapril and Endothelium-Dependent and -Independent Vasodilation
Thirty minutes after completion of the investigation of minimal FVR, baseline hemodynamic measurements were obtained. Next, sodium nitroprusside (6 µg/min per 1000 mL forearm tissue) was infused into the brachial artery, and measurements were repeated in the third minute of infusion.

After FBF returned to baseline (20 to 30 minutes), resting hemodynamic measurements were again assessed. Then, acetylcholine (0.8, 10, 40, and 160 µg/min per 1000 mL) was infused for 3 minutes each,¹¹ and FBF was measured in the last minute of each infusion. BP and heart rate were recorded immediately after completion of each infusion.

Statistical Analysis
Results are shown as mean±SD. One-factor ANOVA was used to test for differences attributable to the different drugs. The influence of cilazapril on BP and responses to acetylcholine infusions were analyzed with profile analysis for repeated measures. Paired and unpaired Student's t tests and linear regression analysis were used as appropriate. A two-tailed probability value of less than .05 was considered statistically significant. All calculations were performed with the StatView II statistical program (Abacus Inc).

	Results

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ACE inhibition by cilazapril was well tolerated, and as shown in Fig 1, casual sitting BP decreased from 151±14/99±7 mm Hg during placebo treatment to 138±17/89±8 mm Hg after 20 weeks of cilazapril (P<.01). Similar decreases were observed for intra-arterially recorded BP values (144±11/80±7 versus 130±14/72±9 mm Hg, P<.01). Heart rate remained unchanged. The decrease of BP was associated with a reduction of resting FVR from 42.2±12.6 to 37.1±10.6 U (P<.05).

View larger version (20K): [in this window] [in a new window]   Figure 1. Casual sitting BP before and during 20 weeks of therapy with cilazapril (5 mg BID) in subjects with primary hypertension. Values are mean±SD of 22 subjects. **P<.01 compared with placebo by profile ANOVA.

The results of the studies during ischemic forearm exercise are summarized in Fig 2. Forearm ischemia was applied for 5.8±1.3 minutes and increased FBF during the placebo study from 2.6±0.8 to 39.3±14.6 mL/min per 100 mL; calculated FVR decreased from 42.2±12.6 to 3.0±1.1 U (P<.001). After 20 weeks of cilazapril, FBF increased nonsignificantly compared with the placebo study to 42.2±10.8 mL/min per 100 mL, but minimal FVR decreased significantly by 15.9±20.2% (from 3.0±1.1 to 2.4±0.7 U, P<.05). The change in minimal FVR did not correlate with age, estimated duration of hypertension, or treatment-induced changes of BP.

View larger version (23K): [in this window] [in a new window]   Figure 2. Effects of cilazapril (5 mg BID) on intra-arterial mean BP, maximal FBF, and calculated minimal FVR in subjects with primary hypertension. Note the nonsignificant increase of maximal FBF, which resulted in the presence of a significantly decreased BP in a significant reduction of minimal FVR. Values are mean±SD of 22 subjects. *P<.05, **P<.01, 20 weeks of cilazapril vs placebo.

Brachial artery infusions of acetylcholine and sodium nitroprusside did not affect BP, heart rate, or contralateral FBF, indicating a lack of systemic effect of regional drug infusions. Sodium nitroprusside as an endothelium-independent vasodilator increased FBF during placebo from 2.6±1.0 to 11.4±5.9 mL/min per 100 mL and decreased FVR from 45.8±22.1 to 13.4±13.4 U; this effect remained essentially unchanged after cilazapril therapy. For the whole group, brachial artery acetylcholine infusions (endothelium-dependent vasodilator) increased FBF from 2.8±1.3 to a maximum of 21.5±17.8 mL/min per 100 mL and decreased FVR from 42.2±12.6 to 11.9±13.6 U. As shown in Fig 3, this response did not differ after cilazapril therapy. Individual changes in vascular responsiveness to acetylcholine were not related to age or cilazapril-induced decreases of BP. Since the potential for improvement of endothelium-mediated vasodilation would appear greatest in those subjects with the most markedly impaired pretreatment acetylcholine response, the effects of cilazapril were analyzed separately in subjects with a maximal acetylcholine-induced vasodilator response below the mean response (n=13). As in the total study group, the vascular response to acetylcholine in this subgroup of subjects was also not influenced by cilazapril, that is, FBF increased from 2.1±0.8 to 7.1±3.5 mL/min per 100 mL before cilazapril therapy and from 2.3±1.0 to 7.6±5.5 mL/min per 100 mL after.

View larger version (19K): [in this window] [in a new window]   Figure 3. Endothelium-dependent vasodilation before and after cilazapril (5 mg BID) in subjects with primary hypertension. Endothelium-dependent vasodilation was assessed as changes of FVR to graded brachial artery infusions of acetylcholine (0.8, 10, 40, and 160 µg/min per 1000 mL). Although cilazapril reduced baseline (before acetylcholine) FVR, it did not influence the decrease of FVR induced by acetylcholine infusions. Values are mean±SD of 22 subjects. *P<.05, 20 weeks of cilazapril vs placebo.

Likewise, when subjects were divided into groups with more severe hypertension (BP at end of placebo period, 157.0±13.7/104.8±3.6 mm Hg, n=10) or milder hypertension (146.1±11.5/95.7±4.3 mm Hg, n=12), there was no difference in the acetylcholine response.

	Discussion

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The results of the present study demonstrate that ACE inhibition with cilazapril is associated with a reduction of minimal FVR, whereas endothelium-dependent vascular relaxation did not change. The decrease of minimal FVR is compatible with a regression of vascular hypertrophy¹⁷ or a step toward reversal of what has been termed vascular remodeling.²⁶ This change may be of importance not only for the regulation of BP but, possibly, also during long-term therapy for the prevention of hypertension-associated vascular complications. The observation that the vascular acetylcholine response was unchanged by cilazapril with the regimen used is similar to findings obtained in human hypertensive arteries after 1 year of cilazapril²² or captopril²⁷ therapy, suggesting that cilazapril, like other antihypertensive therapy,^{23 24} may not be able to influence this aspect of endothelial function in humans. Although these findings therefore are not entirely new, they have been obtained in the same subjects, thereby combining both structural and functional aspects of therapy in vivo.

Decrease of Minimal FVR
Arterial hypertension in humans and animal models of hypertension is associated with increased medial thickness of the arterial resistance vessels, which importantly contribute to the main hemodynamic disturbance in hypertension, that is, elevated peripheral vascular resistance.¹⁷ Recent evidence suggests that actual medial hypertrophy in hypertensive resistance arteries can explain only a fraction of the encroachment of the lumen and that the greater part of this disturbance is due to a reduction in external diameter, a finding termed remodeling,²⁶ that appears to apply also to human essential hypertension.²⁸

We determined changes of minimal FVR as an indirect measure of vascular changes in hypertension. This approach seems justified because this measure correlates closely with structural changes of small resistance arteries assessed directly by a micromyographic technique²⁵ and is not influenced by acute changes of baseline perfusion or BP.²⁹ Thus, it is likely that indirect and direct evaluations of vascular morphology would give similar results. Minimal FVR in our hypertensive subjects was higher than in hypertensive patients in the above-mentioned study,²⁵ indicating that structural changes presumably were present in the forearm circulation of our subjects.

The consequences of such vascular structural changes may be far-reaching because they may not only be of importance for the maintenance and/or progression of hypertension independent of the initiating factor³⁰ but may also contribute to the morbid consequences of the hypertension.³¹ Accordingly, normalization of vascular structure may be a highly desirable aim for antihypertensive treatment. Our finding agrees well with a significant reduction in the media-to-lumen ratio of small hypertensive arteries obtained by buttock biopsies after 1 year of cilazapril therapy²² and the decrease of minimal FVR observed in a group of eight patients treated for 1 year with captopril and additional hydrochlorothiazide in five patients.²⁷ We used the ACE inhibitor cilazapril, which effectively lowered BP^{22 32} ; the reduction in baseline FVR after 20 weeks suggests that the decrease of BP by cilazapril was due to vasodilatation. Interestingly, changes of minimal FVR and BP did not correlate, which would be in line with the contention that ACE inhibition rather than the reduction of BP per se was a key factor underlying this vascular response. An important role of Ang II and possibly of the vascular renin-angiotensin system in the pathogenesis of vascular changes is suggested by experiments documenting a separation of BP and vascular effects of Ang II^{21 33} and an increased vascular renin activity in spontaneously hypertensive rats.³⁴ Moreover, ACE inhibition given early in life was able to prevent the vascular hypertrophy of resistance vessels of spontaneously hypertensive rats.^{35 36} However, other data show that the degree of BP reduction and not the type of therapy may be important for the reversal of cardiovascular structural changes.^{27 37 38} The lack of a control group in the present study obviously prevents firm conclusions regarding the importance of BP reduction versus decreases of Ang II levels in mediating this effect. However, in contrast to cilazapril, the ß-blocker atenolol did not affect the vascular structure of small arteries from hypertensive patients despite similar BP control.²² Therefore, although an improvement of vascular structural changes occurred after cilazapril, it remains to be shown whether such changes significantly improve the prognosis in hypertension independently of BP reduction.

Endothelial Vasodilator Function
Apart from structural changes of resistance vessels, several functional aspects of the regulation of vascular resistance appear to be disturbed in human hypertension,^{39 40 41} among them, impaired endothelium-dependent vasodilatation in response to muscarinic stimulation.^{11 12 13} However, impairment of endothelial vasodilator capacity does not seem to be a ubiquitous finding in human hypertension.¹⁴ The reason for this is not clear.⁴² Nevertheless, it is widely believed that functional changes of the endothelium may be markers of early atherosclerosis.^{8 9 43} Accordingly, the normalization of endothelial function by cilazapril but not hydralazine in animals²⁰ seemed to point to differential effects of antihypertensive drugs on a potentially important aspect of antihypertensive therapy.

Although BP was effectively lowered in the present study, the vascular response to acetylcholine did not change. Therefore, these results are at variance with previous reports of the beneficial effects of antihypertensive therapy regarding the reversal^{20 44 45} or prevention⁴⁶ of endothelial dysfunction in various animal models of hypertension and of acute administration of captopril¹³ in humans. Our results, however, resemble those of another study in hypertensive patients in whom an ACE inhibitor was used alone or in combination in only 3 of 15 patients.²³ In addition, neither the sulfhydryl group–containing ACE inhibitor captopril nor the non–sulfhydryl group–containing compound enalapril administered for 2 months improved endothelium-dependent vasodilation in hypertensive patients.²⁴ Finally, the response of human hypertensive arteries to acetylcholine in vitro was unchanged after 1 year of cilazapril therapy.²² Thus, the present results are compatible with the contention that cilazapril does not have an effect on the endothelial vasodilator response to acetylcholine.

There is no ready explanation for these discrepancies, but several aspects related to the study design and patient population have to be considered. We did not use a control group, and, thus, we did not evaluate the variability of FBF responses to repeated drug infusions in these subjects. However, repeated acetylcholine and sodium nitroprusside infusions in seven normotensive volunteers obtained 4 weeks to 8 months apart showed both interventions to be highly reproducible (W.K., 1995, unpublished data) and suggest that methodological problems presumably cannot account for the lack of effect of cilazapril on this aspect of vasomotor function in human hypertension.

Muscarinic stimulation is only one way of evaluating endothelial control of vasomotor tone. Therefore, the results should not be taken to indicate that ACE inhibitors might not affect responses to other endothelium-dependent pharmacological vasodilators, such as substance P or bradykinin, or to physiological stimuli.

It might also be argued that 2 to 5 months of therapy is not long enough to improve endothelial dysfunction. However, cilazapril improved acetylcholine-mediated vasodilatation in spontaneously hypertensive rats after 4 days of therapy,²⁰ and captopril did so after a single dose in humans.¹³ Finally, 1 year of cilazapril therapy in patients with essential hypertension did not affect the acetylcholine response of hypertensive arteries obtained by fatty tissue biopsy,²² which suggests that treatment duration may not have been a decisive factor regarding the lack of effect of cilazapril on endothelial vasodilator capacity in the current study. The disturbed endothelial response to acetylcholine in hypertensive Dahl rats has also been found to depend on the magnitude of BP elevation.⁴⁷ However, we did not see an effect on the vascular acetylcholine response when our subjects were divided into groups with more severe and less severe hypertension. In addition, captopril had a marked potentiating effect on acetylcholine-induced relaxations even in aortic rings from normotensive rats.⁴⁸ Thus, it appears unlikely that the degree of hypertension was a decisive factor in the lack of effect of cilazapril in this study.

The vasodilator response to muscarinic stimulation does not seem to be disturbed in all individuals with hypertension,¹⁴ and the acetylcholine response was not markedly impaired in this study when all subjects were considered. However, cilazapril was also not effective in a subgroup of subjects with reduced acetylcholine response before therapy, in whom the potential for improvement of endothelium-mediated vasodilation would appear greatest. Endothelium-dependent vasodilation was severely and significantly reduced in these subjects (maximal increase of FBF to acetylcholine to 7.1±3.5 mL/min per 100 mL only) compared with normotensive control subjects studied by the same technique in this¹¹ and other^{12 14 49} laboratories (maximal increases of FBF to more than 20 mL/min per 100 mL). Accordingly, the extent of pretreatment endothelial dysfunction probably cannot explain the lack of effect of cilazapril in our subjects.

A cilazapril-induced attenuation of vascular muscle responses to cGMP increases by acetylcholine also might theoretically explain the lack of effect of cilazapril. However, the vascular response to an increase of cGMP by a maximally vasodilating dose of sodium nitroprusside⁵⁰ was unchanged.

Most of the animal and in vitro data were obtained in preparations from large conduit arteries, whereas human data reflect the behavior of resistance vessels. This may reflect a fundamental difference in the response of the endothelium in different sections of the arterial tree to lowering of BP. Species differences also cannot be excluded. Also, studies on the reversibility^{44 45} or prevention⁴⁶ of endothelial dysfunction have usually been carried out in young hypertensive animals, whereas patients in clinical studies often are older and presumably have had hypertension for a longer period of their life span.

The improvement in humans of endothelium-dependent vasodilation after a single dose of captopril¹³ and the lack of effect of chronic cilazapril in this as well as in another study²² are also difficult to reconcile. However, the former was an acute study with testing performed at peak drug action, whereas we investigated endothelium-dependent vasodilation at least 12 hours after the last drug intake. Therefore, we cannot exclude the possibility that an acute effect of ACE inhibition on endothelial vasodilator function exists independent of BP lowering. Finally, we cannot exclude the possibility that the choice of drug and dosage may have influenced our results, although the lack of effect of captopril and enalapril²⁴ seems to suggest that the negative findings with cilazapril may not be related to the compound chosen for study.

Conclusions
The present study provides functional evidence that structural vascular changes of subjects with essential hypertension may regress during antihypertensive therapy with the ACE inhibitor cilazapril. The lack of relationship between the observed vascular changes and reductions of BP would be in line with experimental evidence supporting a role of Ang II in the development and regression of vascular changes. Our findings do not support the view that ACE inhibition by cilazapril influences endothelial vasodilator function, as measured by vascular relaxation to acetylcholine, to a significant degree. Whether this lack of effect on endothelial vasodilator function is specific for the vascular bed or ACE inhibitor chosen for study, whether it represents a fundamental difference between animal models and human hypertension or is related to the duration of therapy, and whether ACE inhibition is more important than lowering of BP per se remain important issues to be clarified.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang II = angiotensin II BP = blood pressure FBF = forearm blood flow FVR = forearm vascular resistance

	Acknowledgments

 
This work was supported by an educational grant from F. Hoffmann–La Roche, Basel, Switzerland.

Received August 17, 1995; first decision September 18, 1995; accepted November 21, 1995.

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