Departments of 1 Clinical Pharmacy and 2 Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555; 3 Division of Pathology, Research Laboratory, National Ureshino Hospital, Ureshino 843-0393; and 4 Department of Information Physiology, National Institute for Physiological Sciences, Okazaki National Research Institutes, Okazaki 444-8585, Japan
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ABSTRACT |
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Ets-1, which stimulates metalloproteinase gene transcription, has a key role in angiogenesis. We first examined whether activated polymorphonuclear leukocytes (PMNs) enhanced angiogenesis through the induction of Ets-1. Addition of activated PMNs to endothelial cells stimulated both in vitro angiogenesis in collagen gel and Ets-1 expression. Both angiogenesis and Ets-1 expression induced by PMNs were reduced by ets-1 antisense oligonucleotide, suggesting that Ets-1 is an important factor in PMN-induced angiogenesis. Although intercellular adhesion molecule (ICAM)-1 and E-selectin are involved in PMN-induced angiogenesis, the mechanisms underlying their roles in angiogenesis have yet to be elucidated. PMN-induced Ets-1 expression was reduced by a monoclonal antibody against ICAM-1 but not E-selectin despite the inhibition of PMN-induced angiogenesis by both antibodies. Moreover, the stimulation of angiogenesis by H2O2 without PMNs was inhibited by a monoclonal antibody to E-selectin but not ICAM-1. These findings suggested that ICAM-1 in endothelial cells may act as a signaling receptor to induce Ets-1 expression, whereas E-selectin seems to function in the formation of tubelike structures in vascular endothelial cell cultures.
endothelial cell; intercellular adhesion molecule-1; Ets-1
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INTRODUCTION |
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ANGIOGENESIS, formation of new blood vessels, occurs under various pathological conditions (8). Especially in inflammatory diseases such as wound healing, chronic inflammation, solid tumor formation, and diabetic retinopathy, angiogenesis has been shown to be involved in maintenance of the inflammatory state by transporting inflammatory cells, nutrients, and oxygen to the site of inflammation (15). In fact, inflammatory tissue contains an abundance of inflammatory cells, angiogenic blood vessels, and inflammatory mediators (17, 18). Although the mechanisms of angiogenesis during inflammation remain unclear, monocytes and macrophages activated by inflammatory stimuli have been shown to induce angiogenesis through production of growth factors and cytokines (19, 33). In addition, we recently found (38) that activated polymorphonuclear leukocytes (PMNs) can also stimulate angiogenesis. Thus not only activated monocytes and macrophages but also activated PMNs seem to have important roles in stimulating angiogenesis in inflammatory diseases.
Ets-1 is a transcription factor that regulates the gene expression of proteases such as urokinase-type plasminogen activator (u-PA), matrix metalloproteinase (MMP)-1, MMP-3, and MMP-9 (11, 14, 27, 34). Many studies have shown that Ets-1 mediates angiogenesis. Iwasaka et al. (14) reported that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) induce Ets-1 expression and Ets-1 stimulates angiogenesis by inducing the expression of u-PA and MMP-1. Moreover, Oda et al. (27) reported that overexpression of Ets-1 in vascular endothelial cells induced angiogenesis in vitro. Thus Ets-1 seems to play a central role in angiogenesis.
PMNs activated during inflammation adhere to endothelial cells (2, 36). The adherence of PMNs to endothelial cells is mediated by adhesion molecules such as E-selectin and ICAM-1 expressed in endothelial cells (9, 12, 39). We previously demonstrated (38) that ICAM-1 and E-selectin are involved in the induction of angiogenesis by PMNs because anti-ICAM-1 and anti-E-selectin antibodies inhibited PMN-induced angiogenesis. Recently, adhesion molecules have been reported to act as the signaling receptors that mediate changes in intracellular Ca2+ concentration (24) and tyrosine phosphorylation (5). Interestingly, the activation of tyrosine kinase has been reported to be involved in the induction of ets-1 in endothelial cells stimulated by VEGF (30). Therefore, it is possible that the signal transduction from adhesion molecules induces Ets-1 and then stimulates angiogenesis. Alternatively, adhesion molecules may have roles in cell-cell adhesion between endothelial cells in the process of PMN-induced angiogenesis. However, the roles of ICAM-1 and E-selectin in the process of PMN-induced angiogenesis have yet to be elucidated.
In the present study, we found the participation of Ets-1 in PMN-stimulated angiogenesis in bovine aortic endothelial cells (BAECs). Therefore, we investigated the roles of adhesion molecules in the induction of angiogenesis using Ets-1 expression and stimulation of angiogenesis with PMNs.
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METHODS |
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Cell culture. BAECs were obtained by scraping the luminal surface with a razor blade and cultured as described previously (37). Endothelial cells were characterized by microscopic observation and incorporation of acetylated low-density lipoprotein labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (13). Cells at passages 3-8 were used for the experiments.
Preparation of PMNs. PMNs were collected from male Wistar rats (6-8 wk old; Saitama Animal Supply, Saitama, Japan) as previously described (38). Each rat was injected intraperitoneally with 5 ml of 0.5% oyster glycogen in saline. After 4 h, the rats were injected intraperitoneally with 4 ml of 100 U/ml heparin. The cells infiltrating the abdominal cavity were collected with 50 ml of phosphate-buffered saline (PBS) containing 10% fetal bovine serum (FBS). After centrifugation (170 g) for 10 min at 4°C, the supernatant was discarded and the remaining red pellet was subjected to hypotonic lysis by addition of 0.2% NaCl. After 30 s, the lysate was made isotonic by addition of an equal volume of 1.6% NaCl solution and centrifuged at 170 g for 10 min. The supernatant was discarded, and the residual pellet was washed twice with 10 ml of PBS containing 0.1% FBS. The pellet was then suspended in 2 ml of minimum essential medium (MEM) containing 0.1% FBS. The purity of PMNs was confirmed by May Grünwald-Giemsa staining (>95%).
Tube formation assay. Tube formation was measured in 24-well culture plates with the three-dimensional culture method described in our previous report (38). Collagen gel solution (0.5 ml) consisting of a mixture of 8 volumes of type I collagen solution (Koken, Tokyo, Japan), 1 volume of 10-fold concentrated MEM, 1 volume of 0.05 N NaOH, 200 mM HEPES, and 260 mM NaHCO3 was poured into each well of the culture plates and incubated for 60 min at 37°C. The BAEC suspension (5 × 105 cells/ml) in 1 ml of MEM containing 10% FBS was added to the wells and cultured. When the cultures reached confluence, the medium was replaced with MEM containing 0.1% FBS. After 48 h, various numbers of PMNs with or without 1 µM N-formylmethionyl-leucyl-phenylalanine (FMLP) were added and incubated for 3 days at 37°C. Mouse anti-human ICAM-1 (CD54) monoclonal antibody (50 µg/ml; Immunotech, Marseille, France) and mouse anti-human E-selectin (CD62E) monoclonal antibody (50 µg/ml; Pharmingen, San Diego, CA) were added 15 min before PMN treatment. The cultures were washed three times with PBS and fixed with 2.5% glutaraldehyde in PBS. Randomly selected fields measuring 0.86 × 1.3 mm were photographed in each well under phase-contrast microscopy. Tube formation was quantified from three randomly selected fields per experiment by measuring the total additive length of all cellular structures including all branches with a computer-assisted image analyzer (MCID; Imaging Research).
Diffusion chamber assay. To examine whether activated PMNs stimulate in vivo angiogenesis, we used a diffusion chamber assay system modified to assess in vivo angiogenesis as previously described (35). The diffusion chamber was made from a chamber kit purchased from Millipore (Bedford, MA). A cellulose membrane filter (0.45 µm, 14-mm diameter) was glued to each side of the ring chamber with MF (Millipore) cement. Male Wistar rats (200-250 g) were anesthetized by intraperitoneal injection of pentobarbital sodium (10 mg/rat). Before chamber implantation, the backs of the animals were depilated and disinfected with tincture of iodine. The chambers containing PMNs or vehicle were implanted into a subcutaneous pocket in the back of the rats. Seven days after implantation, the chambers were removed from the animals and fixed with 10% formalin solution.
Northern blot hybridization.
BAECs were grown to 90% confluence in MEM containing 10% FBS and
antibiotics, and then the cultures were starved in MEM containing 0.1%
FBS for 48 h. PMNs stimulated with or without FMLP were added to
the cultures and incubated for various periods. Total RNA was extracted
from BAECs by a modified guanidinium isothiocyanate method with ISOGEN
(Nippon Gene, Tokyo, Japan). Aliquots of 20 µg of total RNA were
separated by electrophoresis through 1% agarose-formaldehyde gels. The
RNA was transferred onto Hybond-N nylon membranes (Amersham Pharmacia
Biotech, Little Chalfont, UK) and hybridized with the indicated random
prime-labeled cDNA probes (Amersham Life Sciences). The rat
ets-1 probe was a 1.4-kb BamHI fragment of
ets-1 cDNA cloned into the pLXSN plasmid vector.
Hybridization was carried out for 1 h at 68°C in ExpressHyb
hybridization solution (Clontech, Palo Alto, CA). The membranes were
finally washed in a solution containing 1.7 mM NaCl, 1.7 mM sodium
citrate, and 0.1% SDS at 50°C for 40 min and exposed to BioMax film
(Kodak, Rochester, NY) at 80°C for 48 h. The membranes were
stripped and rehybridized with glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) cDNA, a constitutively expressed gene. The cDNA probe for GAPDH
was prepared by reverse transcription-PCR as described previously
(32). The primer pairs used for amplification of GAPDH
were 5'-TCCACCACCCTGTTGCTGTA-3' and 5'-ACCACAGTCCATGCCATCAC-3'. The PCR
product was electrophoresed through a 1.5% agarose gel, and the
GAPDH-specific band was extracted with a Qiaex II gel extraction kit
(Qiagen K. K., Tokyo, Japan). The signal intensity was quantified
with an imaging analyzer (Image Hyper II; DigiMo, Osaka, Japan).
SDS-PAGE and Western blotting. Confluent BAECs in 10-cm culture dishes were starved of serum for 48 h and treated with PMNs stimulated with 1 µM FMLP. The cells were washed twice with ice-cold PBS and lysed in lysis buffer [20 mM Tris · HCl (pH 7.4), 0.1% SDS, 1% Triton X-100, 1% sodium deoxycholate, and 1 mM p-amidinophenylmethanesulfonyl hydrochloride] for 30 min on ice. The cell lysates were centrifuged at 12,000 rpm for 5 min at 4°C. After the supernatants were collected, the protein concentration was determined with a DC protein assay kit (Bio-Rad Laboratories, Hercules, CA). Samples containing equal amounts of protein (40 µg) were separated on 10% SDS-polyacrylamide gels under reducing conditions and transferred onto Trans-Blot nitrocellulose membranes (Bio-Rad). Nonspecific binding was blocked with 0.2% Aurora blocking reagent (ICN Biomedicals, Costa Mesa, CA) in PBS containing 0.1% Tween 20 for 60 min. The membranes were incubated for 1 h with a 1:1,000 dilution of rabbit polyclonal anti-human Ets-1 (Santa Cruz Biotechnology, Santa Cruz, CA), a 1:1,000 dilution of mouse anti-human ICAM-1 (Zymed Laboratories, San Francisco, CA), or a 1:1,000 dilution of mouse anti-human E-selectin (Pharmingen, San Diego, CA) antibodies and developed with an enhanced chemiluminescence Western blotting detection system (ECL, Amersham Pharmacia Biotech) with horseradish peroxidase (P)-conjugated second antibodies. As the second antibody, a 1:5,000 dilution of P-conjugated goat anti-rabbit IgG (Bio-Rad) for the anti-Ets-1 antibody or a 1:5,000 dilution of P-conjugated goat anti-mouse IgG (Zymed Laboratories) for anti-ICAM-1 and anti-E-selectin antibody was used. The membranes were exposed to chemiluminescence-sensitive film (Hyperfilm, Amersham) for 3-30 s. Densities of signals on the blots were measured with an image analyzer (ImageHyper II).
Statistical analysis. Results are expressed as means ± SE of n observations for each experiment. Statistical analysis was performed with the Bonferroni-Dunn procedure after ANOVA. Differences between means were considered significant at P < 0.05.
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RESULTS |
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In vivo angiogenesis induced by PMNs.
We previously reported (38) that PMNs stimulate in vitro
angiogenesis. To determine whether PMNs induce in vivo angiogenesis, diffusion chambers containing PMNs (1 × 105 cells/ml)
were implanted in the backs of rats for 7 days. Typical morphology of
PMN-induced angiogenesis is shown in Fig.
1. In the surrounding tissues of control
chambers containing saline, newly formed vessels were not observed
(Fig. 1A). Implantation of the chamber containing activated
PMNs induced the formation of a forestlike network of neomicrovascular
vessels. Moreover, membrane hyperplasia and bleeding from the periphery
of neovascular vessels were observed (Fig. 1B), suggesting
that PMNs can stimulate angiogenesis not only in vitro but also in
vivo.
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Induction of Ets-1 expression by PMNs.
We examined whether PMNs stimulated ets-1 mRNA and/or
protein expression in endothelial cells. As shown in Fig.
2A, PMNs (1 × 105 cells/ml) induced ets-1 mRNA expression in
BAECs and the activation of PMNs by FMLP additionally increased the
ets-1 mRNA expression compared with PMNs alone. However,
addition of FMLP to BAECs in the absence of PMNs did not affect
ets-1 mRNA expression (Fig. 2A). The induction of
ets-1 mRNA expression by activated PMNs was dependent on PMN
number at 1 × 104 and 1 × 105 cells
(Fig. 2B). To determine the time course of ets-1
mRNA expression, BAECs were exposed to activated PMNs for various
periods (0-12 h). The induction of ets-1 mRNA
expression started from 1 h after addition of activated PMNs, and
the peak was observed at 3 h after addition (Fig. 2C).
To further clarify the induction of Ets-1 in BAECs stimulated by PMNs,
the level of Ets-1 protein was also examined by Western blotting. The
increase in Ets-1 protein was also observed at 3 and 6 h after
stimulation with activated PMNs (Fig. 3).
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Effects of ets-1 antisense oligonucleotide on PMN-stimulated
angiogenesis and Ets-1 expression.
To investigate whether ets-1 plays a role in PMN-induced
angiogenesis, the effects of ets-1 antisense oligonucleotide
were examined (Fig. 4). Typical
morphological changes of BAECs are shown in Fig. 4,
A-C. BAECs cultured with 0.1% FBS formed some tubelike
structures (Fig. 4A). Addition of activated PMNs by
treatment of BAECs with FMLP markedly enhanced the formation of
tubelike structures with a network of branching cellular cords beneath the surface of the monolayer (Fig. 4B). The activated
PMN-induced tube formation was inhibited by 3 µM ets-1
antisense oligonucleotide (Fig. 4C). The effects of
ets-1 antisense oligonucleotide on activated PMN-induced
angiogenesis are summarized in Fig. 4D. Activated PMNs
stimulated angiogenesis in BAECs, and the angiogenesis was significantly blocked by ets-1 antisense but not by sense or
mismatch oligonucleotides (Fig. 4D). Moreover, the activated
PMN-induced ets-1 mRNA and Ets-1 protein expression were
significantly decreased by treatment with 3 µM ets-1
antisense oligonucleotide but not by sense or mismatch oligonucleotides
(Fig. 5, A and B).
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Effects of antibodies to adhesion molecules on ets-1 mRNA
expression.
We previously reported (38) that FMLP treatment enhanced
adhesion of PMNs to BAECs and the adhesion was inhibited by treatment with 1 µM anti-E-selectin and anti-ICAM-1 antibodies. Furthermore, we
showed (38) that PMN-induced angiogenesis was strongly
inhibited by anti-ICAM-1 and anti-E-selectin antibodies. To confirm the expression of ICAM-1 and E-selectin expression in endothelial cells,
immunoblotting for ICAM-1 and E-selectin was performed (Fig.
6). Weak ICAM-1 expression was observed
in BAECs under basal conditions, and the addition of activated PMNs to
BAECs enhanced ICAM-1 expression from 1 to 6 h after addition
(Fig. 6A). E-selectin expression was also enhanced by
activated PMNs from 18 h after addition (Fig. 6B).
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Effects of antibodies to adhesion molecules on
H2O2-induced angiogenesis.
We previously reported (37) that addition of
H2O2 to BAECs enhanced angiogenesis. To
determine the roles of ICAM-1 and E-selectin in the induction of
angiogenesis by stimulation of endothelial cells without PMNs, the
effects of anti-ICAM-1 and anti-E-selectin antibodies on
H2O2-induced angiogenesis were examined (Fig.
8). H2O2-induced
angiogenesis was inhibited in a concentration-dependent manner by
treatment with anti-E-selectin antibody but not by anti-ICAM-1 antibody
(Fig. 8, A and B). Moreover, the expression of
ets-1 mRNA induced by H2O2 was not
inhibited by either antibody (Fig. 9).
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Effects of superoxide dismutase or catalase on ets-1 mRNA
expression in BAECs stimulated with PMNs.
To investigate the role of H2O2 released from
PMNs in stimulation of Ets-1 expression, the effects of catalase and
superoxide dismutase (SOD) on ets-1 mRNA expression
stimulated by PMN were studied. Activated PMN-induced
ets-1 mRNA expression was inhibited by catalase but not by
SOD (Fig. 10).
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DISCUSSION |
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Our previous study (38) showed that PMNs stimulate angiogenesis in BAECs. However, the mechanisms underlying induction of PMN-induced angiogenesis remained unclear. The initiation of angiogenesis requires digestion of the extracellular matrix via induction of protease activities for endothelial cell migration into the interstitial space (4). Recently, the transcription factor Ets-1, which regulates the gene expression of proteases such as u-PA, MMP-1, MMP-3, and MMP-9, was shown to mediate angiogenesis induced by VEGF and epidermal growth factor (EGF) (14, 27, 34). In the present study, we found that Ets-1 expression in endothelial cells was stimulated by activated PMNs and both PMN-induced angiogenesis and Ets-1 expression were strongly reduced by ets-1 antisense oligonucleotide. Thus Ets-1 also seems to play a central role in PMN-induced angiogenesis in addition to angiogenic growth factor-induced angiogenesis.
PMNs adhere to endothelial cells via adhesion molecules such as
ICAM-1 and E-selectin. Adhesion molecules were initially thought to
function only in cell adhesion between vascular endothelial cells and
leukocytes (3, 6, 16). However, adhesion of PMNs to
endothelial cells was reported recently to trigger various physiological changes including an increase in intracellular
Ca2+ concentration and activation of transcription factor
nuclear factor-B (1, 7, 22, 25, 28). Our previous study
(38) showed that anti-ICAM-1 and anti-E-selectin
antibodies, which inhibited adhesion between PMNs, prevented
PMN-induced angiogenesis by endothelial cells. In fact, the
expression of ICAM-1 and E-selectin was confirmed on BAECs stimulated
by PMNs. Thus both ICAM-1 and E-selectin seem to be essential factors
for PMN-induced angiogenesis. Importantly, the activated PMN-induced
increase in ets-1 mRNA expression was inhibited by
anti-ICAM-1 antibody but not by anti-E-selectin antibody. ICAM-1 but
not E-selectin might act as a signaling receptor for the induction of
Ets-1. We previously reported (37) that H2O2 stimulates angiogenesis through the
induction of Ets-1. Interestingly, H2O2-induced angiogenesis was inhibited by
anti-E-selectin antibody but not by anti-ICAM-1 antibody. Nguyen et al.
(26) previously reported that formation of tubelike
structures by BAEC cultured on fibronectin-coated plates was inhibited
by antibodies to sialyl LewisX/A and E-selectin. E-selectin
seems to function in capillary morphogenesis via endothelial cell-cell
interaction during angiogenesis. These findings indicate that although
ICAM-1 and E-selectin are essential factors, they have a different
roles in PMN-induced angiogenesis, i.e., ICAM-1 might act as a
signaling receptor for induction of Ets-1 expression, and E-selectin
might act in formation of tubelike structures via endothelial cell-cell adhesion.
The activated PMN-induced ets-1 mRNA expression was further stimulated by treatment with anti-E-selectin antibody. There are several possible mechanisms that could account for these observations. First, the signal from E-selectin by cell-cell adhesion between endothelial cells during formation of tubelike structures may negatively regulate ets-1 mRNA expression induced by activated PMNs. However, this possibility was excluded by the lack of stimulatory effect of anti-E-selectin antibody on H2O2-induced ets-1 mRNA expression, although H2O2 induces the formation of tubelike structures. Second, the signal from E-selectin by the interaction between PMN and endothelial cells may negatively regulate ets-1 mRNA expression induced by activated PMNs. In fact, H2O2-induced ets-1 mRNA expression was not affected by treatment with E-selectin antibody. Thus future studies are needed to determine the role of E-selectin in PMN-induced ets-1 mRNA expression.
Activated PMNs have been shown to release reactive oxygen species (ROS) including H2O2 (11, 21, 23). Our previous studies indicated that H2O2 (0.1-10 µM) stimulates angiogenesis via induction of Ets-1 (37) and that PMN-stimulated angiogenesis was inhibited by catalase but not by SOD (38). PMN-induced ets-1 mRNA expression was also inhibited by catalase. Thus H2O2 released from PMNs seems to be involved in the stimulation of angiogenesis through the induction of Ets-1 expression. In the present study, we used nonstimulated endothelial cells to investigate the mechanisms underlying activated PMN-induced angiogenesis, although the activation of endothelial cells is also necessary for the interaction with PMNs. Importantly, H2O2 has been shown to stimulate the expression of adhesion molecules including ICAM-1 (23, 29). In fact, leukocyte accumulation under inflammatory conditions seems to be mediated by ROS such as H2O2 and superoxide (20, 31). The increase of ICAM-1 protein level was observed ~2 h before stimulation of Ets-1 protein level by treatment with activated PMNs. It is possible that PMN-induced Ets-1 expression is mediated by stimulation of ICAM-1 expression induced by H2O2 released from PMNs. Future studies are needed to determine the role of H2O2 in the regulation of adhesion molecule expression during PMN-induced angiogenesis.
In conclusion, our findings suggest that ets-1, ICAM-1, and E-selectin have critical roles in PMN-induced angiogenesis. ICAM-1 may act as a signaling receptor to induce Ets-1 induction, whereas E-selectin seems to be involved in the formation of tubelike structures via cell-cell interactions between endothelial cells.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Yamamoto, Dept. of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa Univ., 1-5-8, Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan (E-mail: yamagen{at}pharm.showa-u.ac.jp).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpcell.00223.2001
Received 15 May 2001; accepted in final form 3 December 2001.
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