Mutagenesis, Vol. 17, No. 5, 439-444,
September 2002
© 2002 UK Environmental Mutagen Society/Oxford University Press
Comparative potencies of induction of point mutations and genetic duplications by the methylating agents methylazoxymethanol and dimethyl sulfate in bacteria
Department of Biology, College of the Holy Cross, Worcester, MA 01610, USA and 1 Department of Biology, Mercer University, Macon, GA 31207, USA
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Abstract |
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Methylazoxymethanol (MAM) and dimethyl sulfate (DMS) are mutagens whose genetic effects can be ascribed to the methylation of DNA. While both methylate the N7 position of guanine heavily, only MAM strongly methylates the O6 position of guanine. We evaluated the relative effectiveness and specificity of MAM and DMS in bacterial assays for the induction of point mutations and the formation of chromosomal duplications by genetic recombination. Salmonella typhimurium strain TS1121 was used to measure the formation of genetic duplications on the basis of the aroC321 allele and mutations by reversion of the hisG46 allele. Specific base pair substitutions and frameshift mutations were measured in a reversion assay based on lacZ alleles of Escherichia coli. The results show MAM to be the more potent mutagen and DMS the stronger recombinagen in the Salmonella assay. In the lacZ assay DMS induced several classes of base pair substitutions (GC
AT transitions, GCTA transversions and ATTA transversions), as well as lower frequencies of +1, –1 and –2 frameshift mutations. The activity of MAM as a base pair substitution mutagen was more specific than that of DMS, inducing only GCAT transitions. It also induced +G, –G, –A and –CG frameshift mutations, though more weakly than it induced GCAT transitions. Long known as a base pair substitution mutagen, the induction of frameshifts by MAM was unexpected. The results show that both DMS and MAM are effective inducers of base pair substitutions and modest inducers of frameshifts and that DMS exhibits a broader spectrum of mutagenic activity than does MAM. |
Introduction |
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Methylazoxymethanol (MAM) and dimethyl sulfate (DMS) are monofunctional alkylating agents that methylate DNA. DMS almost exclusively alkylates nitrogen sites in the DNA bases, most strongly affecting the N7 position of guanine, followed by the N3 of adenine (Hoffmann, 1980
; Loeb and Preston, 1986). In contrast, MAM distributes methyl groups more broadly, including the O6 position of guanine (Kumari et al., 1985). The ratio of O6-methylguanine to N7-methylguanine has been estimated as 0.003–0.004 for DMS (Zielenska et al., 1989; Vogel,E.W. and Nivard, 1994) and 0.188 for MAM (Kumari et al., 1985). O6-alkylguanine tends to mispair when DNA replicates, causing GCAT transitions (Vogel,E.W. and Nivard, 1994; Seo et al., 2000). In contrast, N7-methylguanine does not mispair, but it has indirect genetic consequences through secondary lesions such as abasic sites (Loeb and Preston, 1986; Zielenska et al., 1989; Laval et al., 1990; Goodman et al., 1993; Vogel,E.W. and Nivard, 1994; Glaab et al., 1999). The structures of MAM and DMS are shown in Figure 1.
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Besides being useful as model compounds for studying mechanisms of mutagenesis, MAM and DMS are of interest as environmental mutagens and carcinogens. MAM is a mammalian metabolite of the colon carcinogen 1,2-dimethylhydrazine (Wolter and Frank, 1982
; Kumari et al., 1985; Nelson et al., 1996). It also occurs in cycad plants in the form of its glucoside cycasin (Morgan and Hoffmann, 1983). Exposure may occur when cycads are used as foods with inadequate processing to remove MAM glycosides (Hoffmann and Morgan, 1984; Kisby et al., 1999). When cycasin is cleaved by the ß-glucosidase activity of gut bacteria (Morgan and Hoffmann, 1983) or specific mammalian tissues, especially brain (Kisby et al., 1999), free MAM is released and can exert its toxicological effects. MAM is carcinogenic (Morgan and Hoffmann, 1983; Zeilmaker et al., 1991) and it is genotoxic in diverse assays (Morgan and Hoffmann, 1983; Hoffmann and Morgan, 1984). It has been reported to induce DNA strand breakage (Kumari et al., 1985), base pair substitutions and SOS induction in bacteria, gene mutations and mitotic recombination in yeast, and germ cell mutations in Drosophila. In mammalian systems it has been shown to induce gene mutations, sister chromatid exchange and unscheduled DNA synthesis in cultured cells and chromosome aberrations both in vitro and in vivo (Morgan and Hoffmann, 1983; Hoffmann and Morgan, 1984). The literature on MAM contains inconsistencies, however, such that positive and negative results are sometimes reported for the same genetic end point or assay (Morgan and Hoffmann, 1983).
DMS is used as a methylating agent in organic chemistry and as a model compound in genetic and toxicological studies (Hoffmann, 1980; International Agency for Research on Cancer, 1999). It is carcinogenic in laboratory animals and probably in humans (International Agency for Research on Cancer, 1999). Its genetic effects include the induction of DNA damage, mutations, genetic duplications and phage induction in bacteria; mutations in fungi, plants, Drosophila, fish and cultured mammalian cells; and cytogenetic alterations in plants, fish and mammalian cells (Hoffmann, 1980; Hoffmann et al., 1988; International Agency for Research on Cancer, 1999).
In this study we measured the relative effectiveness and specificity of MAM and DMS in assays for genetic duplications in Salmonella typhimurium and point mutations in Escherichia coli. The aroC321 assay in Salmonella detects a large genetic duplication that forms by homologous recombination (Hoffmann et al., 1983, 1985, 1989; Hoffmann, 1992). Like other aroC mutants, aroC321 strains are deficient in chorismate synthase. They require phenylalanine, tyrosine and tryptophan. The aroC321 allele is an unusual leaky mutation, in that aroC321 strains give rise to genetically unstable tryptophan-independent (Trp+) derivatives that still require phenylalanine and tyrosine. The unstable Trp+ revertants, which arise at a high spontaneous frequency (>10–4) and give rise to many Trp- segregants, contain two copies of the leaky aroC321 allele, along with a surrounding region that includes sim;30% of the chromosome. Since the duplication forms by recA+-dependent recombination (Hoffmann et al., 1985), its induction can be considered a recombinagenic effect. Strain TS1121, which contains the aroC321 and hisG46 alleles, permits the simultaneous measurement of recombinagenic effects and base pair substitution mutations by selecting for Trp+ and His+ revertants, respectively.
The lacZ reversion assay in E.coli, developed by Cupples and colleagues, detects Lac+ revertants that result from specific base pair substitutions in strains CC101–CC106 (Cupples and Miller, 1989; Josephy, 2000) or frameshift mutations in strains CC107–CC111 (Cupples et al., 1990; Josephy, 2000). Each strain carries a specific lacZ mutation on an F' episome and reverts by a single mutational mechanism. The pattern of reversion in the 11 strains therefore provides a simple measure of the spectrum of mutations induced.
Our results in the aroC321 and lacZ assays are interpreted with respect to the relative potency of mutagenic and recombinagenic effects, methylation of oxygen and nitrogen sites in DNA, SN1 and SN2 mechanisms of methylation, mispairing and non-coding lesions in DNA, and the relationship of specific revertibility to forward mutation spectra.
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Materials and methods |
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Chemicals
MAM (methylazoxymethanol acetate, CAS no. 592-62-1) was purchased from Sigma Chemical Co. (St Louis, MO). DMS (CAS no. 77-78-1) was purchased from Aldrich Chemical Co. (Milwaukee, WI). Since they are unstable in water, aqueous solutions were prepared immediately before treatment.
Bacterial strains
Salmonella typhimurium strain TS1121 (aroC321 hisG46) was used to measure genetic duplications on the basis of aroC321 and reversion of hisG46 (Hoffmann et al., 1985). The lacZ reversion assay was conducted in E.coli strains CC101–CC111, obtained from Dr Claire Cupples (Concordia University, Montreal, Canada) (Cupples and Miller, 1989; Cupples et al., 1990; Josephy, 2000).
Media
Salmonella typhimurium strain TS1121 was grown in Difco Nutrient Broth from single colonies on Difco Nutrient Agar. Cell densities and survival were measured on Vogel–Bonner Medium E (Vogel,H.J. and Bonner, 1956) containing 1.5% Difco Bacto Agar and 2% D-glucose (Maron and Ames, 1983), supplemented with 0.2 mM L-phenylalanine, 0.2 mM L-tyrosine, 0.2 mM L-tryptophan and 0.5 mM L-histidine. Bacteria were plated in 2.5 ml of molten top agar (45°C) on the same medium lacking histidine to select for His+ revertants. Top agar was 0.6% Difco Bacto Agar containing a trace (0.036 mM) of L-histidine and 0.5% NaCl. Dilutions were spread on medium lacking tryptophan to select for Trp+ duplicants. Escherichia coli strains CC101–CC111 were picked from single colonies on LB medium (Sambrook et al., 1989) and cultured in Vogel–Bonner Medium E containing 2% glucose and 15 µM thiamine. The selection medium for quantifying Lac+ revertants was Vogel–Bonner Medium E containing 0.2% 
-lactose as sole carbon source.
aroC321 assay and histidine reversion in Salmonella
Two kinds of chemical exposure were used: treatment of non-growing cells in buffer and treatment in growth medium. In both cases, nutrient broth cultures of strain TS1121 were grown overnight to stationary phase in a shaker at 37°C. To treat non-growing cells, a fresh culture was centrifuged and resuspended in 67 mM phosphate buffer, pH 7. Approximately 1.2x109 cells in 300 µl were distributed to Eppendorf tubes containing 300 µl of freshly prepared solutions of MAM or DMS in the same buffer. The bacteria were treated in a shaker for 90 min at 37°C, centrifuged, resuspended in buffer lacking the mutagen and plated on media selective for His+ revertants and Trp+ duplicants. In the reversion assays, 2x108 cells were plated at all dosages. In duplication assays, plating densities were adjusted between 1x105 and 6x105 cells/plate to correct for anticipated toxicity so as to have approximately equal numbers of viable cells per plate in all cases. Further dilutions were plated on fully supplemented minimal medium to determine survival. To treat growing cells, 10 µl (sim;2x107 cells) of a fresh culture was inoculated into 600 µl of nutrient broth containing MAM or DMS. The bacteria were grown for 16 h in a shaker at 37°C and plated on the same media as for treatments in buffer. Plating was in triplicate and colonies were counted after 44 h at 37°C. Revertant and recombinant frequencies are reported as means with standard errors.
lacZ reversion assay in E.coli
Strains CC101–CC111 derived from single colony isolates were subcultured (10 µl in 5.5 ml) in Vogel–Bonner Medium E containing 2% D-glucose and 15 µM thiamine, grown for 16 h at 37°C, centrifuged and suspended in 50 mM phosphate buffer, pH 7, at 4x109 cells/ml. Treatments were initiated by mixing bacteria 1:1 with fresh solutions of MAM or DMS in the same buffer. After 2 h in a shaker at 37°C, treatments were terminated by the addition of 10 ml of 0.9% NaCl, centrifugation and resuspension in saline. Bacteria were surface plated in triplicate or quadruplicate on minimal lactose medium to select for Lac+ revertants.
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Results |
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The genetic activity of MAM in S.typhimurium strain TS1121 is shown in Table I
. MAM causes dose-dependent increases in the frequencies of Trp+ and His+ colonies, indicating the induction of genetic duplications and base pair substitution mutations, respectively. Table II shows the recombinagenic and mutagenic effects of DMS in the same assay. Like MAM, DMS causes dose-dependent increases in the frequencies of both homologous recombination and point mutations.
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Both compounds exhibit dose-dependent toxicity in strain TS1121, but DMS is toxic at lower concentrations than MAM. The difference in toxicity impedes a comparison of the two compounds at equal concentrations in a short-term treatment in buffer. While the mutagenic effect of DMS occurs at a lower absolute concentration, it is weaker than that of MAM when compared at comparable levels of toxicity. Moreover, a comparison at similar concentrations in growing bacteria (e.g. 2 mM) suggests that MAM is the more effective mutagen and DMS the more effective recombinagen. Even when compared at similar toxicities, MAM does not surpass DMS in recombinagenicity. The comparison of mutagenic and recombinagenic potencies is clearest when calculated as slopes of induced recombinational events per induced mutation: 36–57 for MAM and 262–705 for DMS. Thus, the aroC321 assay shows DMS to be highly recombinagenic relative to its mutagenic activity, whereas MAM is a more potent mutagen than a recombinagen.
Table III shows the spectrum of reversion induced by MAM in the lacZ reversion assay. MAM is a potent inducer of GCAT transitions in CC102, but it elicited no response in any of the other base pair substitution strains. It also induced +G, –G, –A and –CG mutations in the frameshift tester strains. The frameshift mutagenicity of MAM is weaker than its induction of transitions. Table IV shows the spectrum of reversion induced by DMS under the same conditions. Statistically significant, dose-dependent increases in revertant frequency were observed in strain CC102, which detects GCAT transitions, strain CC104, which detects GCTA transversions, and strain CC105, which detects ATTA transversions. Thus, DMS exhibited a broader spectrum of mutagenic activity than MAM in the lacZ reversion assay. The responses to DMS in the transversion strains were weaker than those in strain CC102. DMS was also mutagenic in four of the five strains that revert by frameshift mutations: +G frameshifts in CC107, –G frameshifts in CC108, –CG frameshifts in CC109 and –A frameshifts in CC111. On the basis of numbers of induced revertants at a given dosage or fold increase over numbers of spontaneous revertants, the frameshift mutagenicity is small relative to the prominent induction of base pair substitutions.
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Discussion |
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Differences among alkylating agents in mutagenicity and carcinogenicity have long been ascribed to the relative SN1 and SN2 character of the reaction mechanisms (Osterman-Golkar et al., 1970
; Lawley, 1974; Hoffmann, 1980; Vogel,E. and Natarajan, 1982; Zielenska et al., 1989; Elespuru et al., 1991; Glaab et al., 1999). Agents with a high Swain–Scott substrate constant (Swain and Scott, 1953), such as DMS (Vogel,E.W. and Nivard, 1994), have been described as typical SN2 alkylating agents that selectively methylate highly nucleophilic sites, such as base nitrogens in DNA (Hoffmann, 1980; Zielenska et al., 1989). In contrast, agents such as N-methyl-N-nitrosourea (MNU) that have a lower Swain–Scott constant (Vogel,E.W. and Nivard, 1994) and alkylate oxygen sites have been described as having more SN1 character (Zielenska et al., 1989). Loechler (1994) has argued persuasively that interpreting the mutagenicity of alkylating agents with respect to SN2 and SN1 mechanisms is incorrect. His reasoning is supported on several grounds, notably including evidence that all the commonly discussed alkylating agents act through SN2 mechanisms and that the Swain–Scott principle does not properly describe the distribution of alkyl groups in DNA. With highly reactive alkylating agents such as N-ethyl-N-nitrosourea, oxygen sites are disproportionately affected relative to what one might expect on the basis of their relative nucleophilicity. Loechler suggests that `high oxyphilic' versus `low oxyphilic' would be better descriptors than SN1 and SN2 for the reactions of alkylating agents with DNA.
Differences between MAM and DMS in recombinagenic and mutagenic potencies and in mutation spectra can be explained by their patterns of alkylation of DNA. Following the terminology of Loechler (1994), MAM is a highly oxyphilic mutagen whereas DMS is not. The difference is reflected in the O6/N7 ratio of alkylation: sim;0.188 for MAM (Kumari et al., 1985) and 0.003–0.004 for DMS (Zielenska et al., 1989; Vogel,E.W. and Nivard, 1994). O6-methylguanine tends to mispair with thymine, causing GCAT transitions (Seo et al., 2000). Unlike the mispairing bases O6-alkylguanine and O4-alkylthymine (Richardson et al., 1987; Zielenska et al., 1989; Seo et al., 2000), other alkylated bases exert their genetic effects indirectly through secondary, non-coding lesions. N7-methylguanine and N3-methyladenine tend to undergo depurination, which produces abasic sites (Loeb and Preston, 1986; Laval et al., 1990; Vogel,E.W. and Nivard, 1994; Glaab et al., 1999), and N7 methylation triggers ring-opening, producing formamidopyrimidine derivatives (Laval et al., 1990; Glaab et al., 1999). Abasic sites hinder replication (Goodman et al., 1994) and they give rise to base pair substitutions (Goodman et al., 1993, 1994; Glaab et al., 1999), including transitions (Glaab et al., 1999) and especially GCTA transversions (Loeb and Preston, 1986; Laval et al., 1990; Strauss, 1991). Mutagens also stimulate inducible responses that process DNA damage, sometimes giving rise to mutations in doing so. The mutagenic consequences are well known for some of these responses, such as the SOS system, but less so for others. DMS has been shown to induce UVM (Humayun, 1998), an inducible response designated `UV modulation of mutagenesis' that is independent of the SOS and adaptive responses and processes non-coding lesions into mutations (Wang et al., 1995).
The large increases that we observed in the frequency of His+ revertants at non-toxic concentrations in the Salmonella assay (Table I
) confirm earlier studies showing that MAM is a potent mutagen (Morgan and Hoffmann, 1983). The specificity of its base pair substitution mutagenesis for strain CC102 in the lacZ assay (Table III) is consistent with the finding that 23 of 24 forward mutations recovered in the lacI gene after treatment of E.coli with MAM acetate in a mouse host-mediated assay were GCAT transitions (Zeilmaker et al., 1991). Our finding that MAM induces several classes of frameshift mutations is unexpected. Most assays of MAM for frameshift mutagenesis have been negative (Morgan and Hoffmann, 1983), though there is an isolated positive result with mammalian metabolic activation in an Ames assay in Salmonella strain TA1538 (Simmon, 1979).
Like previous studies, our results (Tables II and IV) indicate that DMS is a base pair substitution mutagen. The modest frameshift mutagenicity of DMS is also compatible with earlier studies, in that DMS has given both weakly positive and negative results in assays for frameshift mutations (Hoffmann, 1980). A forward mutation spectrum determined for DMS in the lacI gene in E.coli (Zielenska et al., 1989) showed a predominance of base pair substitutions (111 of 121 mutations). They were primarily GCAT transitions (90/111), followed in frequency by GCTA transversions (14/111) and a few ATGC transitions (3/111) and ATTA transversions (4/111). The forward mutation spectrum is therefore similar to our results in the lacZ reversion assay, in which DMS induced predominantly GCAT transitions with lesser induction of GCTA and ATTA transversions (Table IV). In contrast to DMS, the oxyphilic methylating agent MNU induced exclusively GCAT transitions (39/39) in the gpt gene of E.coli (Richardson et al., 1987), a spectrum compatible with our finding that GCAT was the only base pair substitution induced by the oxyphilic MAM in the lacZ reversion assay.
Abasic sites resulting from depurination of N7-methylguanine and N3-methyladenine (Loeb and Preston, 1986) can explain the induction by DMS of GCTA and ATTA transversions, respectively, as adenine is preferentially inserted opposite abasic sites (Loeb and Preston, 1986; Strauss, 1991). The induction of GCAT transitions by DMS is harder to explain and is apt to involve multiple mechanisms. While there is relatively little O6-methylguanine produced, DMS is an effective alkylator, and a small fraction of the methyl groups are on this position (Zielenska et al., 1989; Vogel,E.W. and Nivard, 1994). These infrequent but highly mutagenic lesions probably contribute to the GCAT transitions. Transitions may also stem from the major alkylation products through depurination, as bases other than adenine are sometimes inserted opposite abasic sites (Loeb and Preston, 1986; Strauss, 1991). In a study of depurination in E.coli, thymine was inserted half as frequently as adenine opposite abasic sites resulting from the loss of guanine by depurination, making it the second most frequently inserted base (Kunkel, 1984). Thus, the yield of GCAT transitions following DMS treatment may reflect an accumulation from mispairing of rare O6-methylguanine residues, insertion of thymine opposite sites of depurination and, perhaps, other less well characterized mechanisms.
A conceptual question about the use of specific reversion assays is whether they provide information comparable to more laborious forward mutation assays or whether other influences, most notably effects of neighboring bases and the general sequence context, are so prominent that reversion assays cannot provide a realistic sense of the mutation spectrum. Sequences may differ in specificity because the efficiency of bypass of abasic sites and of insertion of bases is influenced by neighboring bases (Goodman et al., 1994). However, in the case of MAM and DMS in the lacZ reversion assay (Tables III and IV), the results for base pair substitutions are compatible with published forward mutation spectra (Zielenska et al., 1989; Zeilmaker et al., 1991). The similarity suggests that neighboring base influences are relatively small or that lacZ strain CC102 fortuitously mimics the most sensitive sequence in forward mutation assays (Zielenska et al., 1989; Goodman et al., 1994) in having a purine residue (G in CC102) 5' to the target base.
A coherent view of the base pair substitution mutagenicity of methylating agents emerges by combining the results for MAM and DMS in the lacZ reversion assay with data reported by Ohta et al. (2000) for methyl methanesulfonate (MMS), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and MNU in the same assay. MMS resembles DMS in methylating nitrogen sites almost exclusively, whereas MNU and MNNG, like MAM, also effectively methylate oxygen sites (Vogel,E.W. and Nivard, 1994). The base pair substitutions induced by MNU and MNNG were 97 and 96% GCAT transitions, respectively (Ohta et al., 2000). In contrast, only 56% of the mutations induced by MMS were GCAT transitions, and there was a substantial increase in transversions: 22% ATTA and 16% GCTA (Ohta et al., 2000). Thus, both data sets indicate that oxyphilic alkylators (e.g. MAM) are more specific for GCAT transitions than non-oxyphilic alkylators. The greater proportion of transversions among the mutations induced by MMS in the study of Ohta et al. (2000) than by DMS in our study may be ascribable to their using uvrA pKM101 strains, in that the mucAB genes carried by pKM101 enhance the induction of transversions more strongly than transitions (Watanabe et al., 1994).
By using strains CC107–CC111, we observed that MAM and DMS induce frameshift mutations, though more weakly than they induce base pair substitutions. The modest induction of frameshifts may be ascribable to these agents stimulating or stabilizing slipped mispairing (Streisinger et al., 1966; Hoffmann and Fuchs, 1997) in the repetitive target sites of the lacZ frameshift strains. It is also possible that the frameshift mutagenesis occurs indirectly through the saturation of mismatch repair, as proposed by Cupples et al. (1990) for ethyl methanesulfonate and MNNG in the lacZ reversion assay.
The potent mutagenicity of MAM in the Salmonella assay (Table I) and its induction of GCAT transitions in the lacZ assay (Table III) are probably ascribable to O6 methylation, whereas the broader spectrum of base pair substitutions induced by DMS (Table IV) undoubtedly encompasses mechanisms more indirect than mispairing, including the processing of apurinic sites. The strong recombinagenicity of DMS (Table II) suggests greater dependence on absolute amounts of DNA damage, including depurinating lesions, than on mispairing lesions. N7 methylation, while less mutagenic than O6 methylation, is probably effective in stimulating the recombinational change that leads to genetic duplications.
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Acknowledgments |
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We thank Dr Claire Cupples for the E.coli strains of the lacZ reversion assay, Dr Ronald Jarret for valuable discussions and Mrs Darlene Colonna for excellent secretarial assistance. We also acknowledge the support of the Anthony and Renee Marlon Professorship in the Sciences (G.R.H.) and the undergraduate research participation program of the College of the Holy Cross (D.J.C. and P.J.T.).
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2 To whom correspondence should be addressed. Tel: +1 508 793 3416; Fax: +1 508 793 2696; Email: ghoffmann{at}holycross.edu
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References |
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Received on February 11, 2002; accepted on May 7, 2002.
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