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  1. The controversy came from the finding that, on the one hand, several mutations, including those located in the mutational hotspot region, seem not to impair NOTCH3 activity, and that, on the other hand, all the mutations cause misfolding and aggregation of NOTCH3, which may inactivate the receptor, and a few mutations unambiguously result in a loss of NOTCH3 activity nolvadex reduce puffy nipples

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