(Circulation. 1996;93:672-682.)
© 1996 American Heart Association, Inc.
Articles |
From the Departments of Medicine (K.D.O., A.C.), Surgery (M.D.A.), and Pathology (T.O.M., C.E.A.), University of Washington, Seattle.
| Abstract |
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Methods and Results Immunohistochemistry was performed on 99 coronary artery segments (34 controls and 65 with atherosclerotic plaque) to identify E-selectin, ICAM-1, VCAM-1, macrophages, smooth muscle cells, and T lymphocytes. For each segment, the presence or absence of adhesion molecule was determined at the arterial lumen, on intimal neovasculature, and on intimal nonendothelial cells. Each segment was scored for intimal macrophage and T-lymphocyte densities on a semiquantitative scale of 0 to 3. In atherosclerotic plaques, the prevalences of E-selectin, ICAM-1, and VCAM-1 on plaque neovasculature were twofold higher than their prevalences on arterial luminal endothelium. E-selectin was the only adhesion molecule for which expression on arterial luminal endothelial cells was more prevalent in plaques than in control segments. Increased plaque intimal macrophage density was associated with expression of VCAM-1 on neovasculature (P<.01) and on nonendothelial cells (P<.01). Increased plaque intimal T-lymphocyte density was associated with the presence of both ICAM-1 and VCAM-1 on neovasculature (both P<.01) and on nonendothelial cells (both P<.01).
Conclusions In atherosclerotic plaques, the expression of all three leukocyte adhesion molecules was more prevalent on intimal neovasculature than on arterial luminal endothelium. Further, the presence on neovasculature and nonendothelial cells of VCAM-1 and ICAM-1 was strongly associated with increased intimal leukocyte accumulation. These findings suggest that leukocyte recruitment through and/or activation of intimal neovasculature may play important roles in the pathogenesis of human atherosclerosis.
Key Words: arteriosclerosis adhesion molecules immunohistochemistry endothelium vasculature
| Introduction |
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Recently, several observations from studies of human atherosclerotic plaques have refocused attention on the potential role of intimal neovasculature in atherogenesis. These include (1) identification of the mononuclear cellspecific adhesion molecule VCAM-1 on neovasculature of a large proportion of atherosclerotic plaques, suggesting that leukocytes may be recruited into the plaque through neovessels9 ; (2) demonstration that plasma proteins are present in intimal tissue surrounding plaque neovasculature, suggesting that these vessels could serve as a route for deposition of plasma proteins13 ; and (3) demonstration that macrophages surrounding plaque neovessels may express a molecule implicated in angiogenesis, aFGF, also referred to as FGF-1, suggesting that inflammatory cells might influence the growth of these vessels.14 In addition, the study that documented a high prevalence of neovasculature VCAM-1 in atherosclerotic segments further demonstrated that this adhesion molecule was detected with a much higher prevalence on neovasculature than at the arterial luminal surface of atherosclerotic plaques.9 This latter finding raised the possibility that plaque neovasculature might be a particularly important site for leukocyte recruitment into plaques. Although both ICAM-16 8 and E-selectin8 have been detected on arterial luminal endothelial cells in human atherosclerosis, no studies to date have examined systematically whether or not they also are expressed on plaque neovasculature. In addition, the relation of adhesion molecule expression at various sites in the arterial intima to intimal leukocyte content has not been evaluated.
Thus, the present study was undertaken to determine, in human coronary arterial segments, (1) the relative prevalence of each adhesion molecule in atherosclerotic compared with control coronary segments; (2) whether, like VCAM-1, the adhesion molecules ICAM-1 and E-selectin also are present on neovasculature of atherosclerotic plaques; and (3) whether adhesion molecule expression is associated with increased intimal macrophage and T-lymphocyte content.
| Methods |
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Six-micrometerthick tissue sections of the arterial segments were used for immunohistochemical analyses. The 99 coronary artery segments were classified according to conventional histological criteria into (1) atherosclerotic plaque, defined by the presence of typical features of luminal narrowing due to regional accumulation of cholesterol, foam cell and nonfoam cell macrophages, and the presence of fibrous caps or (2) control coronary segments with intimal accumulation of smooth muscle cells and matrix, which represents the characteristic morphology of nonatherosclerotic, adult, human coronary arteries.15 Of 34 coronary segments classified by morphological criteria as controls, the majority (20 [59%]) were from patients with IDCM, and the remainder (14 [41%]) were from patients with ISCM. Of 65 coronary segments classified by morphological criteria as atherosclerotic plaque, only 10 (15%) were from patients with IDCM, and the majority (55 [85%]) were from patients with ISCM.
Antibodies and Antisera
Polyclonal E-selectin antiserum. Goat
polyclonal
antiserum directed against E-selectin was a gift of Drs R. Lobb and C.
Benjamin, Biogen, Cambridge, Mass.16 The
immunohistochemical specificity and sensitivity of the antiserum were
determined by the following criteria: (1) positive immunohistochemical
staining of E-selectintransfected but not of untransfected CHO
cells; (2) positive immunohistochemical staining of tonsil and of
myocardial biopsies with rejection; and (3) abolition of positive
staining on tonsil, myocardium, and coronary
arteries by absorption of the E-selectin antiserum against
E-selectintransfected CHO cells. This antiserum was used at a
titer of 1:2000.
ICAM-1 monoclonal antibody. A monoclonal antibody against ICAM-1, 1D8, was a gift of Drs John Harlan, University of Washington, and Tim Carlos, University of Pittsburgh. This antibody was generated as described previously.17 The immunohistochemical specificity and sensitivity of the antibody were determined as follows: (1) positive immunohistochemical staining of ICAM-1transfected but not of untransfected CHO cells; (2) positive immunohistochemical staining of tonsil and of myocardial biopsies with rejection; and (3) abolition of positive staining on tonsil, myocardium, and coronary arteries by absorption of the ICAM-1 antibody against ICAM-1transfected CHO cells. This antibody was used at a titer of 1:500.
Polyclonal VCAM-1 antiserum. Rabbit polyclonal antiserum directed against VCAM-1 was a gift of Drs R. Lobb and C. Benjamin, Biogen.18 The immunohistochemical sensitivity and specificity of the VCAM-1 antiserum have been described extensively in a previous report.9 This antiserum was used at a titer of 1:4000.
Cell typespecific monoclonal antibodies. Cell-type
identification was performed by use of the following commercially
available antibodies: anti
-actin19
(Boehringer Mannheim), used at a titer of 1:1000, which in this
context is specific for smooth muscle cells, and anti-CD68 (Dako Corp),
used at a titer of 1:1000, which recognizes
macrophages.18
T-lymphocyte antiserum. T lymphocytes were identified with CD3 antiserum (titer, 1:100) generated in rabbits, which recognizes the common T-lymphocyte receptor CD3.20
Apolipoprotein B antibody. Apolipoprotein B was detected with antibody 9A, which recognizes an epitope located near the LDL receptorbinding region of apolipoprotein B-100. The antibody was used at a titer of 1:1000 and was a gift of Dr Santica Marcovina of the Northwest Lipid Research Laboratory, Seattle, Wash.
Lectins. The lectin Ulex europaeus I, which binds to a fucose moiety on, and thereby recognizes, endothelial cells,21 was used at a titer of 1:1000 as described previously.9
Single-Label Immunohistochemistry
Single-label
immunocytochemistry was performed as described
previously9 22 using the primary antisera,
antibodies, or
lectin. Briefly, tissue sections were deparaffinized with xylene and
rehydrated with graded alcohols. The slides were blocked with 3%
hydrogen peroxide; washed with PBS; incubated for 60 minutes with the
primary antiserum, antibody, or lectin; and then washed again with PBS.
A biotin-labeled secondary antibody, either anti-rabbit (for
VCAM-1 or CD3 antiserum), anti-goat (for E-selectin antisera),
anti-mouse (for anti
-actin or anti-CD68), or
anti-Ulex, then was applied for 30 minutes, followed
by an avidin-biotin-peroxidase conjugate (ABC Elite, Vector
Laboratories) for 30 minutes. Standard peroxidase enzyme substrate,
3,3'-diaminobenzidine with nickel chloride, then was added to yield a
black reaction product. The slides were counterstained with methyl
green.
Negative controls included substitution of the primary antiserum, antibody, or lectin with either PBS or irrelevant antibodies to abolish staining.
Characterization of Plaque Leukocyte Content
Each coronary
artery segment was scored for
macrophage and T-lymphocyte content on a semiquantitative scale
ranging from 0 to 3 in which 0 indicated absence of the cell type; 1,
occasional isolated cells; 2, small focal collections of the cell type;
and 3, large foci of the cell type. Scoring was performed independently
by two observers (K.D.O. and T.O.M.) blinded to the results of adhesion
molecule immunohistochemistry, and agreement was nearly 100%.
Statistical Analyses
The significance of differences between
plaque and control
segments in prevalences of individual adhesion molecules in the intima,
adventitia, arterial luminal endothelium,
and nonendothelial cells was tested with Fisher's
exact test if the expected value for any cell was <5 or with Yates'
corrected
2 test if the expected value was
5.
Neovasculature was not detected in any control segments, so adhesion
molecule expression could not be compared between plaque and control
segments at this site. The significance of associations between plaque
macrophage or T-lymphocyte densities and the prevalence of
expression of each adhesion molecule on arterial luminal
endothelial cells, on neovasculature, or on
nonendothelial cells were tested by the
2 test for linear trend in proportions; however,
because no plaque segments with a macrophage score of 1 had
intimal ICAM-1 expression, formal testing of associations of
macrophage score with prevalences of ICAM-1 expression on
arterial luminal endothelial cells,
neovasculature of nonendothelial cells could not be
performed. Statistical analyses were performed with the
SPSS+ statistical program, and values of P<.05
were considered significant.
| Results |
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Further, of 9 patients with ISCM, intimal E-selectin was detected in 5 of 9 patients (56%), intimal ICAM-1 was detected in 8 of 9 patients (89%), and intimal VCAM-1 was detected in 9 of 9 patients (100%), indicating that expression of adhesion molecules was not restricted to the plaques from a few individuals.
Distribution of Adhesion Molecules Within the Intima
The
presence or absence of adhesion molecules at three distinct
anatomic locations within the intima of atherosclerotic and
control coronary segments was determined (1) on
endothelial cells at the arterial luminal
surface, (2) in association with neovasculature of atherosclerotic
segments, and (3) on nonendothelial cells (Table 2
).
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Adhesion molecule expression on arterial luminal endothelial cells. At the arterial lumen, only E-selectin expression was specific for atherosclerosis, since E-selectin was present on arterial luminal endothelial cells in 9 of 65 atherosclerotic segments (14%) but in none of the control segments (P<.03). ICAM-1 was detected on arterial luminal endothelial cells with similar prevalences of 9 of 65 (14%) in atherosclerotic segments and 6 of 34 (18%) in control segments. Similarly, VCAM-1 was detected on arterial luminal endothelial cells in 28 of 65 atherosclerotic segments (43%) and in 14 of 34 control segments (40%). Thus, in these specimens, neither ICAM-1 nor VCAM-1 expression on arterial endothelial cells was associated with histologically identified atherosclerosis. E-selectin expression on arterial luminal endothelial cells was highly specific for atherosclerotic segments, but the prevalence of E-selectin expression at this site was quite low. Therefore, the increased prevalence of adhesion molecule expression in atherosclerotic compared with control intima was due primarily to adhesion molecule expression on neovasculature and on nonendothelial cells rather than at the arterial lumen.
Neovascular adhesion molecule expression. In human coronary arteries, neovasculature that infiltrates into the intima is a characteristic of atherosclerotic segments but is not found in control segments. Of the atherosclerotic segments included in this study, 59 of 65 (91%) had infiltration of neovessels into the intima, which could be identified by examination of hematoxylin-eosinstained sections. The presence of neovascular endothelial cells was confirmed by immunohistochemistry with the lectin Ulex europaeus I on neighboring sections. In contrast, evaluation of hematoxylin and eosinstained sections, as well as of Ulex-stained sections, confirmed that intimal neovessels were not present in any of the segments classified as controls by morphological criteria.
In
atherosclerotic segments, the prevalence of expression of all three
adhesion molecules was approximately twofold higher for neovasculature
than at the arterial luminal surface. For all plaques, the
percentages of atherosclerotic segments with adhesion molecule
expression on neovasculature versus arterial luminal
endothelial cells were as follows: for E-selectin, 28%
versus 14%; for ICAM-1, 25% versus 14%; and for VCAM-1, 69% versus
43% (all, P<.01). If the 6 plaques without neovasculature
are excluded from consideration, the relative prevalences of adhesion
molecule expression on neovasculature versus at the
arterial lumen are, for E-selectin, 31% versus 16%; for
ICAM-1, 28% versus 14%; and for VCAM-1, 76% versus 41%. Therefore,
all three leukocyte adhesion molecules may be detected on neovascular
endothelial cells, consistent with the
hypothesis that the neovasculature may serve as an important route for
inflammatory cell entry into the atherosclerotic plaque. An example of
E-selectin, ICAM-1, and VCAM-1 expression on plaque neovasculature in a
region with infiltration of macrophages and T lymphocytes and
apolipoprotein B deposition is shown in Fig 1
, while Fig
2
shows, at higher magnification, neighboring sections
of another plaque, with neovascular expression of all three adhesion
molecules in a region with prominent accumulation of both
macrophages and T lymphocytes.
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Intimal nonendothelial cell adhesion molecule expression. Both ICAM-1 and VCAM-1 were detected frequently on intimal nonendothelial cells. ICAM-1 was identified on intimal nonendothelial cells in 24 of 65 atherosclerotic segments (37%) but was not present on nonendothelial cells of control intima (P<.01). VCAM-1 was detected on intimal nonendothelial cells in 45 of 65 plaques (61%) but only 4 of 34 control segments (12%) (P<.01). ICAM-1 and VCAM-1 could be detected on subsets of both macrophages and smooth muscle cells. In contrast to VCAM-1 and ICAM-1, E-selectin expression was restricted to endothelial cells; it was not detected on nonendothelial cells in any of the 99 coronary artery segments studied.
Adventitial Adhesion Molecule Expression
Intimal
neovasculature has been shown by postmortem injection
techniques12 and by confocal microscopy13 to
arise almost exclusively from the adventitial vasa vasorum. Although
expression of all three adhesion molecules on adventitial vasa vasorum
was more prevalent in plaques than in control segments (Table
3
), the difference was significant only for ICAM-1.
E-selectin was detected in 17% of plaques versus 6% of controls
(P=.21), whereas ICAM-1 was detected in 34% of plaques
versus 3% of controls (P<.01) and VCAM-1 was detected in
62% of plaques versus 47% of controls (P=.24). An example
of E-selectin, ICAM-1, and VCAM-1 expression on adventitial
endothelium is shown in Fig 1
.
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Relation of Intimal Endothelial Cell Adhesion
Molecule Expression to Intimal Leukocyte Content
Arterial
luminal endothelial cell
adhesion molecule expression and intimal leukocyte content. Due to
insufficient sample sizes, apparent trends between intimal
macrophage content and the percentage of plaques with
expression of E-selectin and ICAM-1 at the arterial lumen
were not formally testable (Table 4
and Fig 3
).
However, these trends are consistent with
the findings of previous studies demonstrating (1) that positive ICAM-1
staining is present on a greater percentage of the
arterial luminal endothelial circumference
in lesion types with significant inflammatory cell content, ie, fatty
streaks and fibrofatty lesions, than in nondiseased segments or fibrous
caps without prominent inflammation6 and (2) that both
E-selectin and ICAM-1 are present in higher percentages both of
plaques and of nondiseased segments without inflammatory
cells.8 In contrast, there was no clear correlation
between expression of VCAM-1 at the arterial lumen and
intimal content of either macrophages or T lymphocytes.
|
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Neovascular adhesion molecule expression and intimal leukocyte
content. No previous studies have examined whether adhesion
molecule expression on neovasculature is related to intimal leukocyte
content. This study found no association between E-selectin expression
and intimal macrophage or T-lymphocyte content. In contrast, a
strong association was found between neovascular expression of VCAM-1
and intimal macrophage content (P<.01). Although
there appeared to be a relation between neovascular ICAM-1 and intimal
macrophage content, it could not be tested for statistical
significance because of small sample size (Table 4
and Fig
4
). Further, strong associations also were found between
neovascular ICAM-1 or VCAM-1 and intimal T-lymphocyte content (both
P<.01). These results suggest that neovascular expression
of the immunoglobulin superfamily adhesion molecules ICAM-1 and VCAM-1
is associated with intimal accumulation of inflammatory cells.
|
Nonendothelial cell adhesion molecule
expression and intimal leukocyte content. A highly significant
association was found between nonendothelial cell
VCAM-1 expression and intimal macrophage content
(P<.01) (Table 4
and Fig 5
). Also,
there was
a highly significant association between
nonendothelial cell expression of both ICAM-1 and
VCAM-1 and intimal T-lymphocyte content (both, P<.01).
Again, although there appeared to be a relation between
nonendothelial cell ICAM-1 and intimal
macrophage content, this association would not be tested for
statistical significance (Table 4
and Fig 5
).
E-selectin was not
detected on any cell type other than endothelial cells.
|
| Discussion |
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This study is the first to demonstrate that E-selectin and ICAM-1 are expressed frequently by plaque neovessels. It also confirms that, in the coronary arterial segments studied, VCAM-1 is expressed frequently by plaque neovessels and suggests that, in these atherosclerotic coronary segments, all three adhesion molecules are twice as prevalent in neovessels as at the arterial lumen. This indicates that the neovasculature, by virtue of upregulated expression of leukocyte adhesion molecules, may be a very important route for inflammatory cell entry into the intima. Demonstration of the presence of adhesion molecules on plaque endothelial cells does not by itself prove that these molecules have actively participated in leukocyte recruitment, but it can, at the very least, be regarded as a marker of "activation"23 of these cells by cytokines or other molecules present in the surrounding intima.
This study also is the first to correlate the degree of inflammatory cell accumulation in atherosclerotic plaques with the prevalence of expression of each of these three adhesion molecules at three different anatomic sites in the intima. Significant correlations were found between the degree of macrophage infiltration and the prevalence of E-selectin and ICAM-1 at the arterial luminal surface. These findings are consistent with the results of a study by Poston et al6 showing that the extent of arterial luminal ICAM-1 staining was greater in types of lesions with inflammatory infiltrates, ie, fatty streaks and fibrofatty lesions, than in types of lesions without inflammatory infiltrates, ie, nonatherosclerotic human arteries or fibrous plaques. Similarly, van der Wal et al8 showed that the prevalence of arterial luminal expression of both ICAM-1 and E-selectin was greater in both atherosclerotic plaques and nonatherosclerotic arterial segments with subendothelial inflammatory infiltrates than in nonatherosclerotic arterial segments without subendothelial inflammation. However, neither of these previous studies evaluated the expression of ICAM-1 or E-selectin on nonendothelial cells or on neovasculature. Finally, there was no correlation in the present study between VCAM-1 expression at the arterial lumen and leukocyte infiltration.
In the present study, a striking association was found between the degree of macrophage accumulation and expression of VCAM-1 on neovasculature and on nonendothelial cells of atherosclerotic plaques. In contrast, there was no relation between macrophage accumulation and E-selectin expression at these sites. The correlation between macrophage accumulation and neovascular VCAM-1 expression not only suggests that this molecule may indeed participate in entry of macrophages into plaques but also demonstrates the potential importance of the neovasculature as a portal for macrophage entry. In addition, the strong correlation between T-lymphocyte accumulation and neovascular ICAM-1 and VCAM-1 expression further underscores the potential importance of the neovasculature as a route for plaque growth. In contrast, the associations between macrophage accumulation and ICAM-1 expression on neovasculature or nonendothelial cells failed to reach statistical significance. Despite progressive increases in the percentage of segments with neovascular and nonendothelial cell ICAM-1 expression with increasing plaque macrophage scores, these associations could not be tested for statistical significance because of the lack of ICAM-1 expression in any segments with a macrophage score of 1.
The factors that mediate expression of adhesion molecules in atherosclerotic plaques are not known, but many have been proposed. These include diet-induced5 and genetic4 hypercholesterolemia, cytokines, minimally or extensively oxidized lipoproteins, and reactive oxygen species. Several studies have demonstrated that atherosclerotic tissue contains a variety of macrophage- and T lymphocytederived cytokines24 25 26 that may upregulate expression of one or all of the three adhesion molecules evaluated in the present study.23 27 Oxidized lipoproteins also are of particular interest, since lysophosphatidylcholine, a phospholipid generated during LDL oxidation, can increase the expression of VCAM-1 on endothelium both in vitro and in vivo28 and exposure of cultured human umbilical vein endothelial cells to oxidized LDL has been shown to increase cell surface expression of ICAM-1.29 The contention that these observations have physiological relevance is supported by the observations of several investigators that oxidation-specific epitopes are present in atherosclerotic tissue of animals30 31 32 33 34 35 36 and humans33 37 38 and by a recent study demonstrating expression by human aortic plaque macrophages of myeloperoxidase, which generates the reactive oxygen intermediate hypochlorous acid (HOCl).39 Finally, reactive oxygen species may themselves play a role in upregulation of VCAM-1 expression.36 40 Further study is needed to determine which of these many potential mediators are actually responsible for adhesion molecule expression in atherosclerosis.
The observation that both ICAM-1 and VCAM-1 frequently are expressed in atherosclerotic lesions has several implications for antiatherogenic strategies that target adhesion molecules. First, it suggests that several factors are likely to mediate expression of leukocyte-recruiting adhesion molecules, so that attempts to decrease adhesion molecule expression by targeting a specific cytokine are likely to fail. Second, because both adhesion molecules are common in atherosclerosis, targeting only one of them may still allow leukocyte recruitment by the other and thus be ineffective.
Determining the role of plaque neovasculature in atherogenesis and
identification of factors that either promote or inhibit its growth may
lead to the development of novel antiatherogenic strategies. Because
plaque neovasculature could provide an important route for lipid
deposition and inflammatory cell infiltration, it most likely results
in plaque growth. Several potentially angiogenic cytokines have
been detected in atherosclerotic plaques, including tumor necrosis
factor-
41 42 and aFGF,14 and could
represent targets for intervention. Vascular
endothelial growth factor is another potent angiogenic
factor43 that is of interest because it is expressed by
vascular smooth muscle cells exposed to platelet-derived growth
factor, transforming growth factor-ß, or
hypoxia44 and can stimulate
revascularization in a rabbit ischemic hind
limb model.45 Alternatively, similarities between
neovascular ingrowth in plaques and angiogenesis in
tumors46 raises the possibility that antiangiogenic
factors such as thalidomide47 or
angiostatin48 might have applications in
atherosclerosis as well.
In summary, the present study confirms that neovessels may be detected in a substantial majority of advanced human atherosclerotic plaques and demonstrates not only that E-selectin, ICAM-1, and VCAM-1 are expressed on neovascular endothelium but also that their expression at this site is twice as prevalent as their expression at the arterial luminal surface. In addition, this study demonstrates that both neovascular and nonendothelial cell expression of ICAM-1 and of VCAM-1 are correlated strongly with increased intimal leukocyte content. Taken together, these data are consistent with the hypothesis that plaque neovasculature represents a significant route for infiltration of leukocytes into advanced atherosclerotic plaques, and they demonstrate that the neovasculature is a site of inflammatory activation. These findings have implications for the potential utility of antiatherogenic strategies that target adhesion molecule expression and also suggest that elucidation of factors that regulate the development of plaque neovasculature might lead to the development of novel antiatherogenic strategies. Finally, these studies raise the question of whether animal models of atherogenesis in which neovasculature is not a feature can provide sufficient insight into the disease in humans.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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| Footnotes |
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Received July 26, 1995; revision received September 19, 1995; accepted October 4, 1995.
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