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However, a conceptual understanding of how<jats:sup>\u2022<\/jats:sup>NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics<jats:italic>in vivo<\/jats:italic>. Key questions still lacking concrete and definitive answers include those related with quantitative issues of its concentration dynamics and diffusion, summarized in the how much, how long, and how far trilogy. For instance, a major problem is the lack of knowledge of what constitutes a physiological<jats:sup>\u2022<\/jats:sup>NO concentration and what constitutes a pathological one and how is<jats:sup>\u2022<\/jats:sup>NO concentration regulated. The ambient<jats:sup>\u2022<\/jats:sup>NO concentration reflects the balance between the rate of synthesis and the rate of breakdown. Much has been learnt about the mechanism of<jats:sup>\u2022<\/jats:sup>NO synthesis, but the inactivation pathways of<jats:sup>\u2022<\/jats:sup>NO has been almost completely ignored. 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