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. Author manuscript; available in PMC: 2008 Aug 1.
Published in final edited form as: Horm Behav. 2007 May 10;52(2):274–279. doi: 10.1016/j.yhbeh.2007.05.004

Oxytocin Has Dose-Dependent Developmental Effects on Pair-bonding and Alloparental Care in Female Prairie Voles

Karen L Bales 1,2, Julie A van Westerhuyzen 1, Antoniah D Lewis-Reese 2, Nathaniel D Grotte 2, Jalene A Lanter 2, C Sue Carter 2
PMCID: PMC1978481  NIHMSID: NIHMS28652  PMID: 17553502

Abstract

The present study examines the developmental consequences of neonatal exposure to oxytocin on adult social behaviors in female prairie voles (Microtus ochrogaster). Female neonates were injected within 24 hours of birth with isotonic saline or one of four dosages of oxytocin (OT). As adults, females were tested in an elevated plus-maze paradigm (a measure of anxiety and exploratory behavior), and for alloparental behavior and partner preferences. At 2 mg/kg OT, females took longer to approach pups, but were the only group to form a statistically significant within-group partner preference. At 4 mg/kg OT, females retrieved pups significantly more frequently but no longer displayed a partner preference; while females treated developmentally with 8 mg/kg spent significantly more time in side-to-side contact with a male stranger than any other treatment group. OT may have broad developmental consequences, but these effects are not linear and may both increase and decrease the propensity to display behaviors such as pair-bonding.

The neuropeptide oxytocin (OT) has been implicated in social behavior in both male and female mammals. OT's peripheral effects include the induction of parturition and milk let-down, while central OT has been associated with the onset of maternal behavior (Pedersen and Prange Jr., 1979;Pedersen et al., 1982;Pedersen and Boccia, 2002), and other positive social behaviors such as pair-bonding (Insel and Hulihan, 1995;Carter and Altemus, 1997;Cho et al., 1999) and male parental care (Bales et al., 2004b). It is also becoming evident that manipulations of OT and a related peptide, arginine vasopressin (AVP) during the perinatal period of life can have life-long implications for social behavior and neuroendocrine function (Stribley and Carter, 1999;Diaz-Cabiale et al., 2000;Carter, 2003;Lipschitz et al., 2003). These exposures can be either endogenous, through responses to touch, warmth (Uvnas-Moberg, 1998) or perhaps through OT in breast milk (Leake et al., 1981); they could also be pharmacological, for example through use of pitocin or an oxytocin antagonist to manipulate labor (Husslein, 2002).

In this context, we have begun to examine the consequences of OT manipulations in early life for subsequent social behaviors and neuroendocrine variables. Because we were particularly interested in the developmental control of social behaviors such as pair-bond formation and biparental behaviors, we chose to study the socially monogamous prairie vole (Microtus ochrogaster). In this species both males and females display parental care and form selective partner preferences indicative of pair-bonding, although the mechanisms for these behaviors may differ between the sexes (DeVries et al., 1996; DeVries and Villalba, 1997). OT may be particularly related to pair-bond formation and parenting behavior in female voles (Liu and Wang, 2003;Olazabal and Young, 2006), and is also associated with mating (Carter, 1992).

Initial studies involved injecting newborn prairie voles with OT at a dosage used in previous studies of rats [1 mg/kg; (Sohlstrom et al., 2000)]. In voles treated with this dosage, the effects of OT manipulations were especially apparent in males. For example, in male prairie voles neonatal OT facilitated pair-bond formation (Bales and Carter, 2003b); neonatal OT was also associated with a later, sexually dimorphic increase in AVP (V1a) receptor binding in the ventral pallidum and cingulate cortex (Bales et al., 2007b). Males of this species treated with an OTA (at 0.1 mg/kg) exhibited decreased levels of parental care (Bales et al., 2004c), a tendency to be less aggressive (Bales and Carter, 2003a), and as adults showed lower levels of V1a binding in the bed nucleus of the stria terminalis, the lateral septum, and the medial preoptic area (Bales et al., 2007b).

In females neonatal treatment with OT (1 mg/kg) was associated in adulthood with an increase in female-female aggression after exposure to a male (“mate-guarding”); however, other behaviors including partner preferences and parental care were not measurably affected by this treatment (Bales and Carter, 2003a;Bales et al., 2004c). Thus, in this series of studies of the developmental effects of OT the most marked behavioral changes were observed in males (Carter, 2003). These studies left open the possibility that female prairie voles were not responsive to the developmental effects of OT or that the dose level of OT previously used in females was insufficient to affect behavior. The present study examines the hypothesis that female prairie voles will show a dose-dependent response to developmental exposure to OT. In this study a single exposure intraperitoneal (i.p.) injection of one of four dosages of OT (1, 2, 4, or 8 mg/kg) or the isotonic saline vehicle was administered to prairie vole pups within 24 hours of birth. We hypothesized that behaviors such as female parental care and pair-bonding that rely on OT would be facilitated by neonatal exposure to OT, and that anxiety, which in adult voles may be reduced by OT (Carter, 1998), would decrease following neonatal exposure to additional OT. The wide range of doses used here was selected because, although the behavioral effects of peptides are often dose-dependent, it is common for the effects of comparatively low versus high doses to differ.

Methods

Subjects and Neonatal Treatments

All procedures adhered to the standards set forth in the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committees at the University of Illinois at Chicago and the University of California, Davis. Subjects were laboratory-bred female prairie voles, descendants of a wild stock originally caught near Champaign, Illinois. Stock was systematically outbred. Prairie voles were maintained on a 14:10 light:dark cycle and allowed food (Purina high-fiber rabbit chow) and water ad libitum. Breeding pairs were maintained in large polycarbonate cages (44 cm long × 22 cm wide × 16 cm high) and provided with cotton for nesting material. At 21 days of age, females were weaned and housed in same-sex sibling pairs in smaller (27 cm long × 16 cm wide × 13 cm high) cages. The same-sex sibling pairs then were housed in a single-sex colony room.

Within 24 hrs of birth, experimental subjects were briefly removed from the cage, sexed, weighed, and toe-clipped for identification. Female voles were randomly assigned to treatment groups, receiving either an intraperitoneal injection of isotonic saline (SAL), 1 mg/kg OT, 2 mg/kg OT, 4 mg/kg OT, or 8 mg/kg OT. Injections were given based on an average weight of a newborn vole pup of 3 grams. All injections were 25.0 μl in volume and administered in a 250 μl gas-tight Hamilton syringe. Other studies have shown that neonatal OT, as administered here, can at 1 mg/kg produce a rapid change in cFos expression (Cushing et al., 2003). Only one female in each litter was given a particular neonatal treatment. An initial set of subjects was studied at the University of Illinois at Chicago; following the move of the first author, a second set of subjects (including appropriate controls) were added to the study at the University of California, Davis. Methods and husbandry at both sites were administered by the first author and were as identical as possible.

Behavioral Testing

During behavioral testing, females were fully adult and sexually mature, although prairie voles are induced ovulators (Carter et al., 1987) and estrus stage was therefore not a concern. At day 55, females were tested in an elevated plus-maze (EPM). The EPM consisted of two open and two closed arms, each 67 cm long and 5.5 cm in width (Insel et al., 1995). Each vole was placed in the neutral area in the center of the EPM, and behavior was recorded for 5 min using Behavior Tracker 1.0 (www.behaviortracker.com). Any vole that jumped or fell off the EPM was immediately replaced and the test finished (this happened 6 times). Statistical analysis was performed both with and without the voles that fell, and their inclusion or exclusion made no difference to the significance of the results. The time spent in the open arm divided by the total time spent in the open and closed arms was analyzed. Following the EPM test, the voles were returned to their home cage. In rats, more time spent in the open arm of the EPM is considered indicative of higher levels of exploratory behavior and lower levels of anxiety. In voles, behavior in the EPM is responsive to changes in state. For instance, mating experience (Insel et al., 1995), treatment with AVP (Dharmadhikari et al., 1997) and neonatal handling (Bales et al., 2007a) are associated with increased time spent in the open arm of the EPM in prairie voles. Auto-grooming, which may also be indicative of anxiety, also was quantified during the EPM test.

On day 62 (1 week later), voles were tested for alloparental behavior in response to a pup. Procedures for testing parental behavior were modeled on previous work done in this lab (Roberts et al., 1998;Bales et al., 2004b;Bales et al., 2004c;Bales et al., 2006). Females were first given 45 min to adjust to an empty testing arena. The test apparatus consisted of two small cages (sizes the same as previously mentioned) connected by a short, clear tube. At the end of the acclimation period, the subject was removed from the testing arena and an unrelated 1−3 day old pup was placed in the front cage. The subject then was placed into the tube, and behavior was recorded for 10 min on videotape. If the test subject displayed aggression towards the pup, the test was stopped immediately, and the pup was removed and returned to its parents. In most cases, the pup was not injured, and this protocol resulted in a full recovery for the pup. Tapes were scored by an experimentally blind observer using Behavior Tracker 1.0 software. Following the test, females were returned to their home cages. Behaviors scored included latency to approach within one inch of the infant, sniffing the infant, retrievals, licking the infant, or non-huddling contact, which indicated that the test animal was touching the infant without engaging in any of the other behaviors.

On day 69 each female was tested for the development of a partner preference following a protocol that has been used extensively to study pair bonding in voles (Williams et al., 1992). The experimental female was exposed to a previously unfamiliar, randomly selected male for a 30-min period. This short cohabitation period was necessary, as a 1-hr cohabitation period was sufficient for the development of female partner preference under our present colony conditions. Cohabitation began between 9 and 10 am near the onset of the light cycle (which was at 6 am). Randomly assigned male and female partners were placed in a neutral cage during this period. Immediately following the cohabitation period, females were placed in a testing apparatus where they were given a choice over a 3-hr test period of spending time with the now familiar partner; with an unfamiliar opposite-sex animal (otherwise comparable to the partner; here called the stranger); or in an empty, neutral cage. Testing was conducted using an apparatus consisting of three identical polycarbonate cages (mouse cages as described above), attached by Plexiglas tubes (7.5 × 16.0 cm). The experimental vole was free to move about the apparatus while the two stimulus voles were loosely tethered within their own separate chambers. It was physically possible for copulation to occur; however, because prairie voles are induced ovulators (Carter et al., 1980;Carter et al., 1987), it was unlikely. In addition, cohabitation periods and testing were monitored to insure that no copulation took place. Tests were recorded in time-lapse video and scored later by an experimentally blind observer on Behavior Tracker 1.0, with the relevant variables being the time spent in physical side-to-side contact with the partner vs. the stranger. Social preferences also were examined as the difference in time spent in side-to-side contact with the partner and time spent in side-to-side contact with the stranger. Following the test, females were returned to their home cage.

Data analysis

Data analysis for continuous variables was carried out by analysis of variance, a.k.a. ANOVA (Littell et al., 1996) in SAS 8.2. Residuals were checked for normality and other conditions and, if non-normal, data were transformed using the log or square root transformations, or analyzed using a non-parametric Kruskal-Wallis test when transformation was unsuccessful (Sokal and Rohlf, 1981). Following significant ANOVA, post-hoc tests were carried out via least-squared means. All tests were two-tailed and significance was set at p < 0.05.

Results

Plus-maze behavior:

Treatment did not affect the ratio of time that females spent in the open arm [divided by time spent in the open arm + time spent in the closed arm; F(4) = 1.07, p = 0.375]. Means ± standard errors for this ratio were as follows (lower ratios reflect more time spent in the closed arm): SAL: 0.32 ± 0.07; 1 mg/kg OT: 0.36 ± 0.08; 2 mg/kg OT: 0.44 ± 0.09; 4 mg/kg: 0.48 ± 0.08; and 8 mg/kg: 0.31 ± 0.06.

Early OT treatment also did not affect time spent in the open arm [F(4) = 1.45, p = 0.226], the closed arm [χ2(4) = 2.43, p = 0.658], the center of the maze [χ2(4) =2.27, p = 0.687], or time spent autogrooming [χ2(4) =3.08, p = 0.544].

Alloparental care:

Proportion of females attacking pups did not differ between treatment groups (Fisher's exact test, p = 0.609). SAL females attacked in 41% of tests, 1 mg/kg OT females 21%, 2 mg/kg OT females 20%, 4 mg/kg OT females 31%, and 8 mg/kg OT females attacked in 27% of tests. Further analyses of individual behaviors were carried out only on females that did not attack pups.

Significant treatment differences were found in the frequency of retrievals [overall ANOVA: F(4) = 3.39, p = 0.015; Figure 1] and in the latency to approach the pup within one inch [overall ANOVA: F(4) = 2.81, p = 0.034; Figure 2]. Females treated with 4 mg/kg OT retrieved significantly more frequently than SAL females (post-hoc test; t = 3.43, p < 0.01), while females treated with 1 mg/kg OT showed a non-significant trend to retrieve pups more frequently (post-hoc test; t = 1.74, p = 0.089). Latency to approach the pup was significantly higher in females treated with 2 mg/kg OT than in SAL females (post-hoc test; t = 2.15, p = 0.036). All other variables did not differ significantly by treatment, and their means and standard errors are presented in Table 1.

Figure 1.

Figure 1

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Effects of early OT treatment on frequency of pup retrievals (overall ANOVA: F(4) = 3.39, p = 0.015). This includes only females that did not attack the pup. Groups which are statistically different according to post-hoc testing are marked with different letters; groups marked with the same letters are not statistically different.

Figure 2.

Figure 2

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Effects of early OT treatment on latency (in seconds) to approach within one inch of the pup (overall ANOVA: F(4) = 2.81, p = 0.034). This includes only females that did not attack the pup. Groups which are statistically different according to post-hoc testing are marked with different letters; groups marked with the same letters are not statistically different.

Table 1.

Means ± standard errors for behaviors displayed during the alloparenting test, for non-attacking females only (non-significant results only; for significant results see Figures 1 and 2).

Saline 1 mg/kg OT 2 mg/kg OT 4 mg/kg OT 8 mg/kg OT
n= 18 n = 11 n = 12 n = 11 n = 8
Sniff (sec) 12.4 ± 2.2 16.5 ± 4.2 11.3 ± 2.7 11.0 ± 2.3 8.3 ± 2.6
Lick (sec) 177.3 ± 44.3 206.5 ± 39.3 119.3 ± 37.8 174.0 ± 34.9 153.3 ± 51.2
Non-huddling contact (sec) 27.7 ± 13.9 45.2 ± 24.2 14.4 ± 6.8 24.1 ± 10.7 15.4 ± 9.9
Huddle (sec) 14.2 ± 8.8 3.5 ± 3.5 11.1 ± 11.1 49.7 ± 18.6 40.8 ± 27.5
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Partner preference behavior:

Early treatment with OT significantly affected the amount of time that females spent in side-to-side contact with a stranger [Figure 3; Kruskal-Wallis test, χ2(4) = 10.76, p = 0.029], but not time spent in side-to-side contact with the partner [Kruskal-Wallis test, χ2(4) = 2.39, p = 0.665] or total time spent in side-to-side contact [Kruskal-Wallis test, χ2(4) = 3.44, p = 0.487].

Figure 3.

Figure 3

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Effects of early OT treatment on preferences for a partner vs. a stranger, measured as proportion of test time spent in side-to-side contact. Proportion of test time spent in side-to-side contact with a stranger differs significantly by treatment [χ2 (4) = 10.76, p = 0.029], as does the difference between time spent with the partner and time spent with the stranger [χ2 (4) = 10.05, p = 0.04].

In post-hoc tests on time spent in side-to-side contact with the stranger, females treated with 8 mg/kg OT spent significantly more time in this behavior than any other treatment group except for the 4 mg/kg OT group (difference from SAL, Mann-Whitney U test, U = 306.00, p = 0.021; from 1 mg/kg OT, U = 211.0, p = 0.01; from 2 mg/kg OT, U = 218.0, p = 0.004; from 4 mg/kg OT, U = 189.0, p = 0.313). In contrast, females treated with 2 mg/kg OT were the only group to exhibit a statistically significant preference for their partner (Figure 3, indicated by an asterisk; t = 2.42, p = 0.031).

We also examined a more synthetic measure of preference (difference between time spent in side-to-side contact with the partner and time spent in side-to-side contact with the stranger). The effect of early OT treatment on this variable was also statistically significant (Kruskal-Wallis test, χ2(4) = 10.05, p = 0.04). Using this measure, females in the 2 mg/kg OT group differed significantly in their pattern of preferences from the 8 mg/kg OT group (Mann-Whitney U test, U = 105.5, p = 0.004), and tended to differ from the SAL group (Mann-Whitney U test, U = 348.5, p = 0.081).

Early treatment with OT also affected time that females spent totally apart from social contact in the empty cage [Kruskal-Wallis test, χ2(4) = 11.89, p = 0.018]. Means and standard errors were as follows: SAL females, 17.4 ± 1.6% time in empty cage; 1 mg/kg OT: 21.9 ± 3.4%; 2 mg/kg OT 20.5 ± 1.9%; 4 mg/kg OT: 19.3 ± 2.5%; 8 mg/kg OT: 11.6 ± 2.2%. The 8 mg/kg OT females spent significantly less time in the empty cage than all other dosages in post-hoc tests (difference from SAL, Mann-Whitney U test, U = 149.0, p = 0.008; from 1 mg/kg OT, U = 121.0, p = 0.037; from 2 mg/kg, U = 99.0, p = 0.001, from 4 mg/kg, U = 121.0, p = 0.032).

Discussion

Research in socially monogamous prairie voles has revealed that both OT and AVP play major roles in the expression of social behaviors, including pair bonding (Winslow et al., 1993;Williams et al., 1994;Cho et al., 1999) and parental behaviors (Wang et al., 1994;Wang et al., 1998;Pedersen and Boccia, 2002;Bales et al., 2004b). In addition, several studies have shown that exposure to these same peptides during development has long-term consequences for neuroendocrine and behavioral systems (Stribley and Carter, 1999;Carter, 2003;Bales and Carter, 2003a;Bales and Carter, 2003b;Bales et al., 2004a;Bales et al., 2004c). The present study is unique in showing long-lasting, dose-dependent changes in social behavior following neonatal OT exposure in female prairie voles.

The tendency to develop social preferences has been used as a defining feature of socially monogamous species (Kleiman, 1977). However, as shown here the expression of preference behavior also is sensitive to early hormonal experiences. In this study, we showed that developmental exposure to exogenous OT can alter female preferences for partners vs. strangers after a brief period of cohabitation (Figure 3). Although in this paradigm the 1 mg/kg dose did not significantly facilitate partner preference formation, exposure to 2 mg/kg was associated in later life with a statistically significant partner preference (although differences from saline controls were only at the trend level). Unexpected in this context is the finding that females treated to higher dosages of OT (4 mg/kg and 8 mg/kg dosages) did not show a preference for the familiar partner. Rather than showing this preference, females in the 8 mg/kg group spent significantly more time in contact with a stranger. Stranger preferences have also been previously demonstrated in female voles which were given exogenous corticosterone (DeVries et al., 1996). In both cases it is possible that state changes in these females (such as changes in emotionality or anxiety) caused them to avoid the familiar partner; however, the partner preference test provides the experimental animal with the option of avoiding either partner, thus avoiding social contact in general. That is not the case here; in fact females from the 8 mg/kg group, in comparison to other groups, spent the least amount of time alone, suggesting that this group was not simply asocial. It is possible that these animals were seeking novelty, or lacked fear of a strange animal. Alternatively, exposure to early OT might have led to the development of neural systems associated with a tendency to seek variety in partners and polygamy.

In the present study, we observed that developmental exposure to OT was associated in adulthood with a dose-dependent tendency to show alloparenting behavior. Behavior in the EPM was not significantly affected. Both behavior in the EPM (Ramos and Mormede, 1998) and parental behavior may be indicative of a reduction in anxiety or fear (Fleming and Leubke, 1981;Fleming and Corter, 1995;Bales et al., 2004c). Although EPM behavior did not differ significantly by treatment, neonatal treatment with OT did affect measures of parental behavior (latency to approach infants, and frequency of retrievals). In another experiment, neonatal exposure to an OT antagonist (OTA, 0.1 mg/kg) affected neural activation to a stressor in later life, as measured by c-Fos expression in the central nucleus of the amygdala (Kramer et al., 2006). These findings support the hypothesis that reactivity to stressful experiences can be permanently altered by developmental manipulations of peptide systems.

In general, the central mechanisms for these changes remain to be investigated. There is considerable evidence from between species comparisons that monogamous and nonmonogamous mammals have differences in the distribution of peptide receptors including those for OT and AVP (Witt et al., 1991;Shapiro and Insel, 1992;Insel et al., 1994). In addition, we have observed that early manipulations of OT, even at the lowest dose used here (1 mg/kg), are capable of producing life-long, sexually-dimorphic changes in peptide receptors (Bales et al., 2007b) . In female prairie voles neonatal treatment with OT reduced vasopressin (V1a) receptor binding in several brain regions including the medial preoptic area, bed nucleus of the stria terminalis, lateral septum, and mediodorsal thalamus, without significantly affecting OT receptors or dopamine D2 receptors. Using, methods similar to those of the present study, Yamamoto et al. (2004) found that early exposure to a single dose (1 mg/kg) of OT produced a significant increase in OT immunoreactivity in the PVN; however, those measurements were taken at weaning (21 days of age) while the females in this study were adult. Another study (Kramer et al., 2006) found that neonatal OT exposure resulted in reduced AVP immunoreactivity in the SON in adult females; in addition, neonatal OTA resulted in increased cFos expression in the central amygdala after exposure to a male. It is possible that changes in either OT or AVP peptide or receptors (or other systems) could be affecting females at different dosages, and that the mechanisms underlying the changes observed here might be different for each dosage.

In summary, the data from this experiment support the hypothesis that early manipulations of OT can have long-lasting behavioral and neuroendocrine effects. The results of the present study revealed that even within an individual the effects of neonatal OT may differ across behavioral measures. In addition, exposure to OT in the neonatal period, although capable of facilitating pup-directed behavior at one dosage, appeared to interfere with – rather than facilitate - the development of preferences for familiar partners at another dosage.

In previous studies, neonatal OT, at 1 mg/kg, tended to either have no effect or to facilitate social behaviors in females (Bales and Carter, 2003a;Bales et al., 2004c). When compared to earlier studies in male prairie voles, the present study suggests that females may differ from males in their sensitivity to neonatal peptide manipulations (Bales and Carter, 2003b;Bales et al., 2004c). The effects of higher doses of OT in males remain unknown. However, there are indications that male reproductive capacity and some aspects of sexual behavior may be disrupted by exogenous neonatal OT even at the 1 mg/kg dosage (Bales et al., 2004a). Earlier studies have revealed that a single exposure to an OTA has long-lasting behavioral and endocrine consequences (Bales et al., 2004a;Bales et al., 2004c). These effects were in general disruptive to behavior and physiology, with the most marked effects seen in males and on the AVP system (Yamamoto et al., 2004;Bales et al., 2007b). However, some negative consequences for sociality, such as a trend to be non-parental (Bales et al., 2004c), and more fearful following OTA (Kramer et al., 2006) also were seen in females.

OT (pitocin) is widely used in obstetrics to facilitate labor and reduce potential postpartum hemorrhage. In addition, OT antagonists are clinically available as tocolytics, for the prevention of prematurity (Husslein, 2002). In both cases the behavioral or neuroendocrine effects for the human infant do not appear to have been investigated (Rojas Wahl, 2004). It is generally assumed that OT does not cross the placenta, although the integrity of this barrier may be affected by the birth process (Laudanski and Pierzynski, 2003). OT also is present in breast milk (Leake et al., 1981), but probably not in formula, and may be lowered by other obstetric practices such as Caesarian section (Nissen et al., 1996). The consequences for infant development of such manipulations have in general not been examined. The results of the present studies support the need for a deeper understanding of the developmental consequences of OT and related peptides.

Acknowledgments

This research was supported by NIH PO1 HD38490 (CSC) and NIH NRSA F32 HD08702 ( KLB), NIMH RO1 073022 (CSC and KLB), and NSF (grant # 0437523, KLB). We thank Tim Hill and Drs. James Artwohl, Cindy Clayton, and Terry Hewett for animal and veterinary care. We also thank Sheryl Katta, Kristin Kramer, Julie Hazelton, Tressia Hing, Alex Kowalczyk, and Mike Ruscio for research assistance.

Footnotes

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